药学学报

Drug name	Degradation target	Related diseases in the study
CC-122 (avadomide)^[7]	Ikaros, Aiolos, ZFP91, ZMYM2	MM, DLBCL, FL, GBM, HCC
CC-99282^[7]	Ikaros, Aiolos	DLBCL, NHL, BCL
CC-220 (iberdomide)^{[7, 17]}	Ikaros, Aiolos	MM, BCL
CC-885^[7]	GSPT1, Aiolos, CDK4, BNIP3L	MM, AML
CC-90009 (eragidomide)^[7]	GSPT1	AML, MDS
CFT7455^[7]	Ikaros, Aiolos	MM, NHL, DLBCL
BTX-1188^[7]	GSPT1, Ikaros, Aiolos, CK1α	AML, NHL, solid tumor
CC-91633^[7]	CK1α	AML, MDS
CC-92480 (mezigdomide)^[7]	Ikaros, Aiolos	MM, TCL
CC-647^[7]	PLZF	APL
CC-3060^[7]	PLZF	APL
DIX-01^[9]	Ikaros, Aiolos, GSPT1	AML
FPT-2216^[10]	Ikaros, Aiolos, CK1α	Lymphoma
MGD-22^[12]	Ikaros, Helios, Aiolos	MM, DLBCL, AML
MGD-28^[11]	Ikaros, Helios, Aiolos, CK1α	MM
NX-2127^[13]	Ikaros, Aiolos, BTK	CLL
KT-413^[14]	Ikaros, Aiolos, IRAK4	DLBCL
Compound 55^[18]	Helios	Cancer
Lead degrader 31^[19]	Helios, CK1α	Cancer
PVTX-405^[20]	Helios	CRC
NVP-DKY709^[21]	Helios	Solid tumor
BC6^[25]	Bcl-6, Ikaros, Aiolos	DLBCL
ALV-07-082-03^[26]	CDK4/6, Helios	T-ALL

Drug name

Degradation target

Related diseases in the study

CC-122 (avadomide)^[7]

Ikaros, Aiolos, ZFP91, ZMYM2

MM, DLBCL, FL, GBM, HCC

CC-99282^[7]

Ikaros, Aiolos

DLBCL, NHL, BCL

CC-220 (iberdomide)^{[7, 17]}

Ikaros, Aiolos

MM, BCL

CC-885^[7]

GSPT1, Aiolos, CDK4, BNIP3L

MM, AML

CC-90009 (eragidomide)^[7]

GSPT1

AML, MDS

CFT7455^[7]

Ikaros, Aiolos

MM, NHL, DLBCL

BTX-1188^[7]

GSPT1, Ikaros, Aiolos, CK1α

AML, NHL, solid tumor

CC-91633^[7]

CK1α

AML, MDS

CC-92480 (mezigdomide)^[7]

Ikaros, Aiolos

MM, TCL

CC-647^[7]

PLZF

APL

CC-3060^[7]

PLZF

APL

DIX-01^[9]

Ikaros, Aiolos, GSPT1

AML

FPT-2216^[10]

Ikaros, Aiolos, CK1α

Lymphoma

MGD-22^[12]

Ikaros, Helios, Aiolos

MM, DLBCL, AML

MGD-28^[11]

Ikaros, Helios, Aiolos, CK1α

NX-2127^[13]

Ikaros, Aiolos, BTK

CLL

KT-413^[14]

Ikaros, Aiolos, IRAK4

DLBCL

Compound 55^[18]

Helios

Cancer

Lead degrader 31^[19]

Helios, CK1α

Cancer

PVTX-405^[20]

Helios

CRC

NVP-DKY709^[21]

Helios

Solid tumor

BC6^[25]

Bcl-6, Ikaros, Aiolos

DLBCL

ALV-07-082-03^[26]

CDK4/6, Helios

T-ALL

Drug name	Degradation target	Related diseases in the study
CC-122 (avadomide)^[7]	Ikaros, Aiolos, ZFP91, ZMYM2	MM, DLBCL, FL, GBM, HCC
CC-99282^[7]	Ikaros, Aiolos	DLBCL, NHL, BCL
CC-220 (iberdomide)^{[7, 17]}	Ikaros, Aiolos	MM, BCL
CC-885^[7]	GSPT1, Aiolos, CDK4, BNIP3L	MM, AML
CC-90009 (eragidomide)^[7]	GSPT1	AML, MDS
CFT7455^[7]	Ikaros, Aiolos	MM, NHL, DLBCL
BTX-1188^[7]	GSPT1, Ikaros, Aiolos, CK1α	AML, NHL, solid tumor
CC-91633^[7]	CK1α	AML, MDS
CC-92480 (mezigdomide)^[7]	Ikaros, Aiolos	MM, TCL
CC-647^[7]	PLZF	APL
CC-3060^[7]	PLZF	APL
DIX-01^[9]	Ikaros, Aiolos, GSPT1	AML
FPT-2216^[10]	Ikaros, Aiolos, CK1α	Lymphoma
MGD-22^[12]	Ikaros, Helios, Aiolos	MM, DLBCL, AML
MGD-28^[11]	Ikaros, Helios, Aiolos, CK1α	MM
NX-2127^[13]	Ikaros, Aiolos, BTK	CLL
KT-413^[14]	Ikaros, Aiolos, IRAK4	DLBCL
Compound 55^[18]	Helios	Cancer
Lead degrader 31^[19]	Helios, CK1α	Cancer
PVTX-405^[20]	Helios	CRC
NVP-DKY709^[21]	Helios	Solid tumor
BC6^[25]	Bcl-6, Ikaros, Aiolos	DLBCL
ALV-07-082-03^[26]	CDK4/6, Helios	T-ALL

Drug name

Degradation target

Related diseases in the study

CC-122 (avadomide)^[7]

Ikaros, Aiolos, ZFP91, ZMYM2

MM, DLBCL, FL, GBM, HCC

CC-99282^[7]

Ikaros, Aiolos

DLBCL, NHL, BCL

CC-220 (iberdomide)^{[7, 17]}

Ikaros, Aiolos

MM, BCL

CC-885^[7]

GSPT1, Aiolos, CDK4, BNIP3L

MM, AML

CC-90009 (eragidomide)^[7]

GSPT1

AML, MDS

CFT7455^[7]

Ikaros, Aiolos

MM, NHL, DLBCL

BTX-1188^[7]

GSPT1, Ikaros, Aiolos, CK1α

AML, NHL, solid tumor

CC-91633^[7]

CK1α

AML, MDS

CC-92480 (mezigdomide)^[7]

Ikaros, Aiolos

MM, TCL

CC-647^[7]

PLZF

APL

CC-3060^[7]

PLZF

APL

DIX-01^[9]

Ikaros, Aiolos, GSPT1

AML

FPT-2216^[10]

Ikaros, Aiolos, CK1α

Lymphoma

MGD-22^[12]

Ikaros, Helios, Aiolos

MM, DLBCL, AML

MGD-28^[11]

Ikaros, Helios, Aiolos, CK1α

NX-2127^[13]

Ikaros, Aiolos, BTK

CLL

KT-413^[14]

Ikaros, Aiolos, IRAK4

DLBCL

Compound 55^[18]

Helios

Cancer

Lead degrader 31^[19]

Helios, CK1α

Cancer

PVTX-405^[20]

Helios

CRC

NVP-DKY709^[21]

Helios

Solid tumor

BC6^[25]

Bcl-6, Ikaros, Aiolos

DLBCL

ALV-07-082-03^[26]

CDK4/6, Helios

T-ALL

Mutation region	Protein	Mutation site	Disease
N	Ikaros	M31V^[91], V52L^[91], V53M^[91], D81N^[91], S105L^[91]	B-ALL
	Helios	R106W^[107]	AOSD
	Aiolos	E82K^[104]	SLE, HT, AIH, asthma
NZF	Ikaros	D120V^[90]	SLE
		N159S^{[91, 93, 102]}	T-ALL, BCP-ALL, CID
		N159T^[93]	CID
		N160S^[101]	CLL
		R162Q^{[99, 102]}	IgAV, CVID, ITP
		R162W^[102]	BCP-ALL
		H167R^[105]	APS
		R183H^[92]	NXG
		L188V^[106]	APS, SLE
		Y210C^[102]	Pancytopenia
		L132P^[97], R143W^[98], H167Y^[100]	CVID
		C147R^[102], H195R^[103], R213^*[96]	ITP
		N159Y^[90], R162P^[91], H163Y^[91], D186fs^[91]	B-ALL
	Helios	Y220^*[94]	CID
	Aiolos	G159R^[101]	EBVAL, DG
		N160S^[101]	MM, DG
		L162R^[104]	CLL
		G191R^[95]	CID
IntZF	Ikaros	S427^*[96]	DG
		S455Rfs^*4^[108]	ND
		D252N^[91], R258P^[91], M306^[91], T333A^[91], G337S^[91], M347V^[91], Y348C^[91], A365V^[91], C394^[91], R423C^[91], A434G^[91], L449F^[91], M459V^[91]	B-ALL
	Helios	N220S^[107]	ES
		R291^*[107]	DG, ITP
		I325V^[109], V347M^[107]	DG
		Y359C^[107]	ITP
	Aiolos	Q402^*[104]	ITP
CZF	Ikaros	C467R^[96]	ES
		M476T^[91]	B-ALL
		M494V^[91]	CNSL
		M494fs^*86^[91]	DG
		R502L^[96]	ITP, BL

Mutation region

Protein

Mutation site

Disease

Ikaros

M31V^[91], V52L^[91], V53M^[91], D81N^[91], S105L^[91]

B-ALL

Helios

R106W^[107]

AOSD

Aiolos

E82K^[104]

SLE, HT, AIH, asthma

NZF

Ikaros

D120V^[90]

SLE

N159S^{[91, 93, 102]}

T-ALL, BCP-ALL, CID

N159T^[93]

CID

N160S^[101]

CLL

R162Q^{[99, 102]}

IgAV, CVID, ITP

R162W^[102]

BCP-ALL

H167R^[105]

APS

R183H^[92]

NXG

L188V^[106]

APS, SLE

Y210C^[102]

Pancytopenia

L132P^[97], R143W^[98], H167Y^[100]

CVID

C147R^[102], H195R^[103], R213^*[96]

ITP

N159Y^[90], R162P^[91], H163Y^[91], D186fs^[91]

B-ALL

Helios

Y220^*[94]

CID

Aiolos

G159R^[101]

EBVAL, DG

N160S^[101]

MM, DG

L162R^[104]

CLL

G191R^[95]

CID

IntZF

Ikaros

S427^*[96]

S455Rfs^*4^[108]

D252N^[91], R258P^[91], M306^*[91], T333A^[91], G337S^[91], M347V^[91], Y348C^[91], A365V^[91], C394^*[91], R423C^[91], A434G^[91], L449F^[91], M459V^[91]

B-ALL

Helios

N220S^[107]

R291^*[107]

DG, ITP

I325V^[109], V347M^[107]

Y359C^[107]

ITP

Aiolos

Q402^*[104]

ITP

CZF

Ikaros

C467R^[96]

M476T^[91]

B-ALL

M494V^[91]

CNSL

M494fs^*86^[91]

R502L^[96]

ITP, BL

Mutation region	Protein	Mutation site	Disease
N	Ikaros	M31V^[91], V52L^[91], V53M^[91], D81N^[91], S105L^[91]	B-ALL
	Helios	R106W^[107]	AOSD
	Aiolos	E82K^[104]	SLE, HT, AIH, asthma
NZF	Ikaros	D120V^[90]	SLE
		N159S^{[91, 93, 102]}	T-ALL, BCP-ALL, CID
		N159T^[93]	CID
		N160S^[101]	CLL
		R162Q^{[99, 102]}	IgAV, CVID, ITP
		R162W^[102]	BCP-ALL
		H167R^[105]	APS
		R183H^[92]	NXG
		L188V^[106]	APS, SLE
		Y210C^[102]	Pancytopenia
		L132P^[97], R143W^[98], H167Y^[100]	CVID
		C147R^[102], H195R^[103], R213^*[96]	ITP
		N159Y^[90], R162P^[91], H163Y^[91], D186fs^[91]	B-ALL
	Helios	Y220^*[94]	CID
	Aiolos	G159R^[101]	EBVAL, DG
		N160S^[101]	MM, DG
		L162R^[104]	CLL
		G191R^[95]	CID
IntZF	Ikaros	S427^*[96]	DG
		S455Rfs^*4^[108]	ND
		D252N^[91], R258P^[91], M306^[91], T333A^[91], G337S^[91], M347V^[91], Y348C^[91], A365V^[91], C394^[91], R423C^[91], A434G^[91], L449F^[91], M459V^[91]	B-ALL
	Helios	N220S^[107]	ES
		R291^*[107]	DG, ITP
		I325V^[109], V347M^[107]	DG
		Y359C^[107]	ITP
	Aiolos	Q402^*[104]	ITP
CZF	Ikaros	C467R^[96]	ES
		M476T^[91]	B-ALL
		M494V^[91]	CNSL
		M494fs^*86^[91]	DG
		R502L^[96]	ITP, BL

Mutation region

Protein

Mutation site

Disease

Ikaros

M31V^[91], V52L^[91], V53M^[91], D81N^[91], S105L^[91]

B-ALL

Helios

R106W^[107]

AOSD

Aiolos

E82K^[104]

SLE, HT, AIH, asthma

NZF

Ikaros

D120V^[90]

SLE

N159S^{[91, 93, 102]}

T-ALL, BCP-ALL, CID

N159T^[93]

CID

N160S^[101]

CLL

R162Q^{[99, 102]}

IgAV, CVID, ITP

R162W^[102]

BCP-ALL

H167R^[105]

APS

R183H^[92]

NXG

L188V^[106]

APS, SLE

Y210C^[102]

Pancytopenia

L132P^[97], R143W^[98], H167Y^[100]

CVID

C147R^[102], H195R^[103], R213^*[96]

ITP

N159Y^[90], R162P^[91], H163Y^[91], D186fs^[91]

B-ALL

Helios

Y220^*[94]

CID

Aiolos

G159R^[101]

EBVAL, DG

N160S^[101]

MM, DG

L162R^[104]

CLL

G191R^[95]

CID

IntZF

Ikaros

S427^*[96]

S455Rfs^*4^[108]

D252N^[91], R258P^[91], M306^*[91], T333A^[91], G337S^[91], M347V^[91], Y348C^[91], A365V^[91], C394^*[91], R423C^[91], A434G^[91], L449F^[91], M459V^[91]

B-ALL

Helios

N220S^[107]

R291^*[107]

DG, ITP

I325V^[109], V347M^[107]

Y359C^[107]

ITP

Aiolos

Q402^*[104]

ITP

CZF

Ikaros

C467R^[96]

M476T^[91]

B-ALL

M494V^[91]

CNSL

M494fs^*86^[91]

R502L^[96]

ITP, BL

Ikaros家族蛋白的研究进展

PDF下载

孙立蕊 , 卢多 ^*

药学学报 | 综述 2026,61(9): 3329-3342

收起

药学学报 |综述 2026 , 61 (9) : 3329 -3342

Ikaros家族蛋白的研究进展

全屏

[Author(id=1320166682094579719, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1320166678047077372, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1320166682195243017, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1320166678047077372, authorId=1320166682094579719, language=EN, stringName=Li-rui SUN, firstName=Li-rui, middleName=null, lastName=SUN, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=State Key Laboratory of Active Substances and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1320166682308489226, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1320166678047077372, authorId=1320166682094579719, language=CN, stringName=孙立蕊, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院北京协和医学院, 药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1320166680584630275, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1320166678047077372, xref=null, ext=[AuthorCompanyExt(id=1320166680597213188, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1320166678047077372, companyId=1320166680584630275, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Active Substances and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1320166680609796101, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1320166678047077372, companyId=1320166680584630275, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院北京协和医学院, 药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])]), Author(id=1320166682379792396, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1320166678047077372, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=luduo@imm.ac.cn, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1320166682459484174, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1320166678047077372, authorId=1320166682379792396, language=EN, stringName=Duo LU, firstName=Duo, middleName=null, lastName=LU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=^*, address=State Key Laboratory of Active Substances and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1320166682526593039, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1320166678047077372, authorId=1320166682379792396, language=CN, stringName=卢多, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=^*, address=中国医学科学院北京协和医学院, 药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1320166680584630275, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1320166678047077372, xref=null, ext=[AuthorCompanyExt(id=1320166680597213188, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1320166678047077372, companyId=1320166680584630275, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Active Substances and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1320166680609796101, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1320166678047077372, companyId=1320166680584630275, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院北京协和医学院, 药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])])]

孙立蕊, 卢多^*

作者信息

中国医学科学院北京协和医学院, 药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050

通讯作者:

卢多，Tel: 86-10-63039979，E-mail: luduo@imm.ac.cn

作者简介:

作者贡献:

孙立蕊负责文献资料收集和综述撰写; 卢多负责指导与修改。

Research progress on Ikaros family proteins

Li-rui SUN, Duo LU^*

Affiliations

State Key Laboratory of Active Substances and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

出版时间: 2026-09-12 doi: 10.16438/j.0513-4870.2026-0512

文章导航

摘要

收起

随着度胺类药物诱导目标效应蛋白泛素化降解的发现, 类似机制的药物研发诸如蛋白降解靶向嵌合体(proteolysis targeting chimera, PROTAC) 在世界范围迅速扩张, 占据新药研发领域相当大的比例。作为最早明确的度胺类药物效应蛋白, Ikaros家族同样得到了更广泛的关注。尽管近些年对于该家族的研究依然聚焦于免疫细胞的发育分化, 但研究关注点在向调节性T细胞(regulatory T cell, Treg) 倾斜。相对应地, 度胺类药物也开始在系统性红斑狼疮为代表的自身免疫性疾病方面进行尝试。作为转录因子, Ikaros家族蛋白的调控机制一直是研究热点。在相关研究中, Ikaros在基因组空间结构组织方面的功能尤为引人关注。本综述首先简要回顾度胺类药物研究进展, 然后总结新发现的Ikaros家族蛋白相关生理功能与分子调控机制。希望通过这些信息的整理分析, 明确相关研究的发展趋势, 探讨进一步靶向Ikaros蛋白家族的可能路径。

关键词

Ikaros家族蛋白 / 度胺类药物 / 生理功能 / 调控机制 / 基因组架构

Abstract

收起

With the discovery that thalidomide-like drugs induce the ubiquitination and degradation of target effector proteins, drug development based on similar mechanisms, such as proteolysis targeting chimera (PROTAC), has rapidly expanded worldwide, occupying a considerable proportion of the novel drug discovery landscape. As the first clearly identified effector proteins of thalidomide-like drugs, the Ikaros family has also garnered broader attention. Although recent research on this family continues to focus on the development and differentiation of immune cells, a particular shift in interest has been observed toward regulatory T cells (Tregs). Correspondingly, thalidomide-like drugs are now being explored for use in autoimmune diseases, such as systemic lupus erythematosus. As transcription factors, the regulatory mechanisms of Ikaros family proteins have long been a research hotspot. Among various findings, the role of Ikaros in organizing genomic spatial architecture stands out as particularly prominent. Here, we first briefly review the research progress on thalidomide-like drugs, and then summarize newly discovered physiological functions and molecular regulatory mechanisms of Ikaros family proteins. By organizing and analyzing this information, we aim to clarify trends in related research and explore potential strategies for further targeting the Ikaros protein family.

Key words

Ikaros family protein / thalidomide-like drug / physiological function / regulatory mechanism / genome architecture

引用本文

孙立蕊, 卢多. Ikaros家族蛋白的研究进展. 药学学报, 2026 , 61 (9) : 3329 -3342 . DOI: 10.16438/j.0513-4870.2026-0512

Li-rui SUN, Duo LU. Research progress on Ikaros family proteins[J]. Acta Pharmaceutica Sinica, 2026 , 61 (9) : 3329 -3342 . DOI: 10.16438/j.0513-4870.2026-0512

正文

收起

Ikaros锌指蛋白家族于20世纪90年代发现, 作为转录因子主要在血系细胞, 特别是淋巴细胞的分化发育方面起重要作用。该家族由Ikaros (编码基因IKZF1)、Helios (IKZF2)、Aiolos (IKZF3)、Eos (IKZF4) 和Pegasus (IKZF5) 5个同源蛋白成员组成。它们在结构上均包含N末端多个锌指模块, 用于结合DNA; 在C末端有另外两个高度保守的锌指, 用于蛋白质间相互作用, 包括家族内部的同源或者异源二聚甚至多聚。同时, 每个家族成员又通过差异剪接演绎出多种异构体蛋白, 携带不同数量的锌指, 具备不同的序列长度。这使得整个家族非常庞大。绝大多数异构体具备C端二锌指区域, 由此通过不同的聚合可能产生大量的复合体形式, 代表着一个非常复杂的调控模式^[1]。为表述清晰起见, 下文中具备全部编码序列的蛋白用全称表示(如Ikaros), 其他截短异构体按照当前学界习惯用缩写字母加编号表示(如IK6)。

Ikaros蛋白家族是度胺类药物的明确效应蛋白。度胺类药物由问题药物转变为治疗多发性骨髓瘤(multiple myeloma, MM) 的新药, 受到许多关注。其诱导目标蛋白经泛素化降解的新颖药物作用机制引领了一大类新型药物的快速涌现, 包括PROTAC药物^[2], 而度胺类药物的成功也表明了靶向Ikaros家族蛋白在可成药性方面的优势。近些年, 度胺类药物的相关研究首先明确了作用机制, 并在此基础上, 一方面探讨导致耐药的机制, 另一方面尝试衍生出新型更高效且特异的化合物用于临床。同时, 得益于对Ikaros蛋白家族的深入研究, 度胺类药物与其他治疗方法联用以及在骨髓瘤以外适应症上的应用也得到了一些有益的尝试。

作为度胺类药物的明确效应蛋白, Ikaros家族蛋白愈发受到关注。当前针对其功能的研究, 在血系细胞(特别是免疫细胞) 分化发育及炎症相关方向有了进一步的深入。此外, 其在调控细胞迁移定位及参与病毒感染表征等方面也取得新进展。血系以外的细胞诸如神经细胞中也发现了Ikaros家族蛋白的作用。病理研究与正常细胞功能研究并行发展。在传统的肿瘤研究之外, 研究人员开始关注一些原发性免疫疾病和自身免疫性疾病。与疾病相关的Ikaros蛋白家族基因突变在不断丰富。

作为转录因子, Ikaros蛋白的上下游调控通路及分子机制自然成为研究热点, 既有利于理解生理功能, 又可以为药物干预疾病发展提供条件。近年来, Ikaros家族蛋白的相关研究在信号通路、转录调控机制及翻译后修饰等方向均取得了阶段性进展。在诸多调控相关研究中, Ikaros蛋白参加调节基因组结构构建的成果显得非常突出, 为探究机制提供了一个全新的视角。

本文尝试汇总近年来Ikaros家族蛋白的研究成果, 包括度胺类药物, 为进一步开展相关研究提供帮助。鉴于度胺类药物经多年研究, 其体系已相对完善, 本文将着重分析新发现的Ikaros家族相关生理功能及分子调控机制, 探讨靶向该蛋白家族的全新方案的可能性。

1　靶向降解Ikaros家族蛋白的度胺类药物

收起

借助结构生物学研究, 度胺类药物介导Ikaros等蛋白底物降解的分子机制已得到清晰阐释。Cullin-RING泛素连接酶4复合物(Cullin-RING ligase 4 complex with cereblon, CRL4CRBN) 利用cereblon (CRBN) 亚基识别蛋白底物, 而度胺药物通过其戊二酰亚胺环结合到该亚基C端结构域上的一个疏水腔中, 诱导底物结合口袋发生构象转变, 识别并捕获底物Ikaros和Aiolos锌指, 进而由复合物催化亚基对其进行泛素化修饰, 最终经蛋白酶体途径降解。底物锌指主要使用其β发卡结构完成与CRBN和度胺药物的互作(图 1)^[3], 而且类似情况同样出现在另外一种底物酪蛋白激酶1α (casein kinase 1 alpha, CK1α) 中^[4]。在大体一致的底物识别模式之上, 不同度胺类药物在结构功能细节上存在差异。相较于泊马度胺, 来那度胺可促使CRBN蛋白346~363氨基酸区域发生构象重排形成两个β-折叠结构。该构象变化最终导致底物特异性的差异: 来那度胺可同时降解Ikaros和CK1α, 而泊马度胺仅对Ikaros有活性^[5]。

值得注意的是Ikaros与Aiolos泛素化修饰位点都在N端锌指区域, 因此理论上讲, 降解只针对含有N端锌指的异构体蛋白, 而不能影响其他异构体, 即度胺类药物诱导的Ikaros蛋白家族降解并没有清除全部基因产物, 而是调整了通过差异剪接所产生的各种异构体在细胞中的比例。度胺类药物介导Ikaros/Aiolos降解, 影响其下游效应分子干扰素调节因子4 (interferon regulatory factor 4, IRF4) 和MYC蛋白(MYC proto-oncogene, c-Myc), 最终导致细胞凋亡^[6]。

在明确的药物作用机制辅助下, 新一代药物从提升CRBN亲和力^[7]、改造降解底物结合界面^{[7, 8]}、靶向多重目标蛋白^[9-14]、增加降解底物选择性^{[15, 16]}等方面进行了许多有益的尝试。目前, 临床进展最好的是CC-220。它比来那度胺或泊马度胺结合CRBN的亲和力更强、抗骨髓瘤活性更好。CC-220联合地塞米松的Ⅰ/Ⅱ期临床试验已顺利完成^[17]。在引起肿瘤细胞凋亡机制之外, 一些研究尝试靶向降解Helios, 通过影响Treg达到抑制免疫逃逸的效果, 用于肿瘤免疫治疗^[18-21]。

与其他药物联用方面也有一些进展, 如来那度胺联用酪氨酸激酶抑制剂或钙调神经磷酸酶抑制剂, 用于拓展度胺药物适用范围^[22-24]。同时, 有研究人员尝试度胺药物与其他药物偶联, 包括B细胞淋巴瘤6 (B-cell lymphoma 6, BCL6)-PROTAC和细胞周期蛋白依赖性激酶4/6 (cyclin-dependent kinase 4/6, CDK4/6) 抑制剂等^{[25, 26]}。来那度胺还被用于辅助嵌合抗原受体T细胞免疫(chimeric antigen receptor T-cell immunotherapy, CAR-T) 疗法^[27]。上述新一代药物相关信息汇总于表 1^{[7, 9-14, 17-21, 25, 26]}。

虽然度胺类药物应用于MM治疗的时间不久, 但耐药现象已经出现。研究显示, 外在和内在两种机制帮助骨髓瘤细胞实现耐药^[28]。外在机制主要是肿瘤微环境的变化^[29]。度胺类药物能在一些患者的浆细胞中诱导程序性死亡配体1 (programmed death-ligand 1, PD-L1) 表达, 进而抑制T细胞, 促使侵袭性骨髓瘤行为及免疫逃逸的发生^[30]。内在机制主要涉及CRBN、药物及Ikaros三者之间的互作。有研究发现, 患者CRBN基因10号外显子剪接缺失导致对度胺药物结合口袋的破坏。小鼠细胞对度胺天然耐药则是源于其药物结合口袋中的一个异亮氨酸(Ile391) 增加了药物结合的空间位阻^[31]。细胞实验显示, CRL4CRBN复合物的泛素结合酶E2 G1 (ubiquitin conjugating enzyme E2 G1, UBE2G1) 亚基失活, 会显著降低来那度胺和泊马度胺诱导的Ikaros与Aiolos的降解程度, 从而导致耐药^[32]。此外, Runt相关转录因子1/3 (Runt-related transcription factor 1/3, RUNX1/3) 等分子可以与CRBN竞争性结合Ikaros/Aiolos, 从而拮抗度胺药物作用^[33]。

有研究显示, 在原本对来那度胺敏感的T细胞淋巴瘤细胞中, 当激活蛋白1 (activator protein 1, AP-1) 的亚基c-Jun被抑制, AP-1与锌指蛋白91 (zinc finger protein 91, ZFP91) 共同作用的基因位点上ZFP91的结合显著增加, 导致下游基因重编程, 由此抵消Ikaros缺失对细胞所造成的毒性效应, 从而导致肿瘤细胞获得性耐药^[34]。除此之外, 还有一些不直接影响CRBN-Ikaros-IRF4信号通路的耐药机制, 感兴趣的读者可以参考Bird与Pawlyn2023年的综述文章^[28]。

随着对Ikaros家族蛋白理解的深入, 度胺类药物的应用也在向肿瘤以外领域扩展。一项随机Ⅱ期临床试验显示在现有狼疮治疗方案基础上联用伊伯多胺(iberdomide), 对亚急性与慢性皮肤红斑狼疮患者具有良好治疗作用^[35]。来那度胺可通过降解Aiolos和Ikaros, 诱导下游一系列基因转录活性的改变, 从而抑制Ⅲ型先天性淋巴细胞(type Ⅲ innate lymphoid cells, ILC3s) 向ILC1s与自然杀伤细胞(natural killer cell, NK) 转分化, 进而调节1型/3型免疫反应^[36]。在结肠炎小鼠模型中, 来那度胺显示出显著疗效^[10]。沙利度胺类似物通过解除Ikaros对人类免疫缺陷病毒(human immunodeficiency virus, HIV) 转录的抑制活性, 展现出针对1型HIV的潜伏逆转功效^[37]。在血红蛋白病治疗中, 泊马度胺通过选择性影响γ-珠蛋白抑制网络, 诱导胎儿样红细胞分化程序, 逆转成人红细胞中γ-珠蛋白沉默, 为β-血红蛋白病患者提供潜在治疗选择^[38]。

2　Ikaros家族蛋白相关的生理功能

收起

针对Ikaros家族蛋白的功能研究已经持续了三十多年, 为度胺类药物的研发提供了多方面支撑。基于探索靶向Ikaros家族全新模式的设想, 本文将重点汇总近些年的研究成果。对早期研究感兴趣的读者可以参考既往的综述文章^[1]。

2.1　Ikaros家族蛋白与适应性免疫

2.1.1　T细胞

Ikaros家族蛋白最初被证实在T淋巴细胞的发育过程中发挥关键作用^[39], 近年来淋巴细胞分化发育领域的研究持续更新, 对其调控机制的阐释更加全面。

在胚胎期T淋巴细胞生成方面, Ikaros通过调控CC趋化因子受体9 (C-C chemokine receptor 9, CCR9) 和IRF4发挥作用^[40]。在初始T细胞响应白细胞介素7 (interleukin-7, IL-7) 方面, Ikaros通过维持叉头盒蛋白O1 (forkhead box protein O1, FoxO1) 表达水平, 辅助IL-7受体α及L-选择素的表达, 进而影响初始T细胞的存活与归巢^[41]。

在T细胞表型调控方面, 抑制Ikaros可直接改变异质性胞核核糖核蛋白L样(heterogeneous nuclear ribonucleoprotein L-like, HNRNPLL) 的表达, 进而影响白细胞共同抗原相关蛋白的亚型转换, 即调节初始表型标志物CD45RA与记忆表型标志物CD45RO的表达^[42]。在使用人工胸腺类器官(artificial thymic organoid, ATO) 体系的研究中发现, 携带Ikaros显性负效应突变(可对活性Ikaros分子进行抑制) 的前体细胞被阻滞于CD4-CD8-双阴性阶段并维持CD45RA⁺表型, 而Ikaros单倍剂量不足细胞表现稍有缓和但仍难以有效发育至CD4⁺CD8⁺双阳性阶段, 且部分细胞存在CD45RA向CD45RO表型转化障碍^[42]。

在辅助性T细胞分化过程中, 早期研究证实Ikaros家族蛋白广泛参与该过程, 尤其对IL-2的转录发挥重要调控作用^[43]。新的研究结果显示, 在缺乏Ikaros时, CD4⁺ T细胞仍能分化为1型辅助性T细胞(type 1 T helper cell, Th1)、Th2和Th17亚群, 但无法分化为诱导性Treg。同时, 上述细胞内促炎细胞因子表达水平显著升高, 进而推动Th17细胞向与自身免疫及病理性炎症相关的表型分化^[44]。

在Treg与Th17之间, 多个Ikaros家族蛋白展现出调节功能。有研究认为Ikaros是Treg中维持耐受性和控制炎症免疫反应所需的核心因子。Ikaros与叉头框蛋白P3 (forkhead box P3, Foxp3) 协同作用, 共同塑造Treg的表观基因组与转录组特征。在炎症性肠病和器官移植模型中, Ikaros缺陷的Treg无法控制由T细胞受体(T cell receptor, TCR) 和炎症刺激诱发的T细胞免疫病理损伤^[45]。

多项研究聚焦于Helios在Treg中的作用。Helios促进人胎儿CD4⁺初始T细胞优先向Treg分化。敲除胎儿初始T细胞中的Helios会削弱其经TCR激活后向iTreg的分化能力^[46]。另有研究认为Helios是Tregs稳定性的标志物, 而非驱动因子, 因为虽然Helios高表达细胞减少、中等表达细胞增多与Treg稳定性下降密切相关, 但敲除人类初始型或记忆型Treg中的Helios基因并未影响其抑制功能及在炎症条件下的稳定性^[47]。

Eos在Treg中的功能同样存在一些争论, 为此研究人员构建了Treg细胞条件性敲除Eos的小鼠模型。该研究中Treg细胞在体外实验中仍然保留其抑制活性, 但是体内实验显示诸多异常: 小鼠在髓鞘少突胶质细胞糖蛋白诱导下表现出严重的实验性自身免疫性脑脊髓炎^[48]。

在银屑病相关研究中发现Helios参与调控Th17细胞分化方面的作用。患者CD4⁺ T细胞中黑色素瘤缺乏因子2 (absent in melanoma 2, AIM2) 缺失可下调IKZF2的表达, 导致Th17标志物视黄酸相关孤儿受体γt (retinoic acid-related orphan receptor gamma t, RORγt) 表达显著上升, Treg标志物Foxp3表达下降^[49]。

除Treg、Th17外, Ikaros家族蛋白同样参与调控滤泡辅助性T细胞(follicular helper T cells, Tfh) 的分化。Tfh分化所必需的转录抑制因子BCL6受到Aiolos、Ikaros与信号转导及转录激活因子3 (signal transducer and activator of transcription 3, STAT3) 的共同调节^[50]。虚拟记忆T细胞的程序化发育过程中, Aiolos通过抑制转录因子脱中胚蛋白(eomesodermin, Eomes) 及IL-15受体亚基CD122的表达而进行负向调控^[51]。在CD4⁺细胞毒性T淋巴细胞分化过程中, Eos发挥正向调节作用, 而Aiolos则通过拮抗STAT5来抑制Eos表达^[52]。

在Th1细胞中, 干扰素γ信号通过激活STAT1诱导Aiolos表达, 而Aiolos可通过调节STAT1启动子处的染色质可及性来提高STAT1的蛋白水平。如此形成持续放大的正反馈信号环路, 驱动趋化因子受体C-X-C基序趋化因子受体3 (C-X-C motif chemokine receptor 3, CXCR3) 的高表达, 使Th1细胞向炎症部位迁移^[53]。

多项研究揭示, Ikaros参与调控T细胞中的磷脂酰肌醇3-激酶(phosphoinositide 3-kinase, PI3K) 信号通路。在T细胞急性淋巴细胞白血病(T-cell acute lymphoblastic leukemia, T-ALL) 细胞中, Ikaros可调控多个PI3K通路相关基因, 整体上发挥对PI3K通路的抑制效应。此外, 酪蛋白激酶2 (casein kinase 2, CK2) 可以通过磷酸化Ikaros与磷酸酶和张力蛋白类似物(phosphatase and tensin homolog, PTEN), 分别破坏它们的DNA结合能力与去磷酸化活性, 从两个途径对PI3K通路实现调控^{[54, 55]}。另外一项关于T-ALL的研究显示, PTEN的表达能够降低一种Ikaros差异剪接异构体(缺失大部分C端锌指) 的蛋白水平, 进而减少在微小RNA-26b (microRNA-26b, miR-26b) 基因上对活性Ikaros异构体的竞争, 促进miR-26b的表达及对其靶蛋白磷脂酰肌醇-4, 5-二磷酸3-激酶催化亚基δ (phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit delta, PIK3CD) 的抑制^[56]。在一项针对多发性硬化症的研究中发现, IL-22通过激活核因子κB (nuclear factor-kappa B, NF-κB) 通路抑制PTEN表达, 由此解除对PI3K的p110α亚基表达的抑制, 导致下游信号分子蛋白激酶B (protein kinase B, Akt) 磷酸化, 进而抑制FoxO1表达。FoxO1的下调抑制了T细胞中Ikaros的表达^[57]。而在ALL细胞中, 缺乏N端锌指的Ikaros异构体IK6作为Akt-FoxO1通路的上游因子, 能够提升Akt和FoxO1的磷酸化水平, 保护细胞免受柔红霉素诱导的凋亡作用影响^[58]。由此Ikaros可以通过PI3K、CK2、PTEN、miR-26b、Akt、FoxO1以及Ikaros异构体蛋白等多个节点在T细胞中参与PI3K通路的调节。

2.1.2　B细胞

Ikaros是调控B细胞发育及功能的核心分子。其核心作用在于通过双重机制维持B细胞正常分化程序: 一方面, 它与配对盒基因5 (paired box 5, PAX5)、早期B细胞因子1 (early B cell factor 1, EBF1)、IRF4等B细胞主调控因子协同, 建立并维持驱动前B细胞分化的超级增强子; 另一方面, Ikaros富集于干细胞-上皮细胞相关基因的非活性增强子区域, 直接抑制跨谱系转录程序。当Ikaros缺失时, 前B细胞分化基因表达受阻, 而本该被抑制的跨谱系因子被异常激活。这些因子重构增强子网络可抵抗多梳蛋白的基因表达沉默作用, 异常引入干细胞-上皮细胞特征, 最终形成兼具干细胞-上皮细胞-B细胞特性的高危白血病前体表型^[59]。

另有研究在前B细胞中发现, Ikaros与STAT5通过竞争相同靶基因的调控序列, 在功能上相互拮抗^[60]。在B细胞急性淋巴细胞白血病(B-cell acute lymphoblastic leukemia, B-ALL) 中, 研究同样显示STAT5对抗NF-κB及Ikaros对下游基因的调控, 同时, STAT5在超级增强子区域显著富集, 与由PAX5、EBF1、富含嘌呤的非特异性结合蛋白1 (purine-rich unspecific binding protein 1, PU.1)、IRF4及Ikaros等转录因子构成的B细胞分化调控网络形成对抗关系。这两种相互拮抗的转录程序一旦失衡, 即成为驱动B-ALL发生的关键机制^[61]。

Ikaros和Aiolos是早期B细胞发育的协同抑制因子, 在小前B细胞中抑制替代轻链基因免疫球蛋白λ样多肽1 (immunoglobulin lambda like polypeptide 1, Igll1) 和前B淋巴细胞基因1 (pre-B lymphocyte gene 1, Vpreb1) 的表达, 导致控制祖B细胞向前B细胞转变的前B细胞受体(pre-B-cell receptor, pre-BCR) 丢失^[62]。Ikaros缺失会导致B细胞分化受阻而停滞在基质黏附的大前B细胞阶段^[63]。

在浆细胞的分化过程中, Ikaros可以与IRF4形成异源二聚体并结合在锌指-IRF复合元件(zinc finger-IRF composite elements, ZICE) 基序上, 对下游靶基因表达进行抑制, 该相互作用是浆细胞分化所必需的^[64]。

Ikaros还是调控B1细胞及脾脏初始B细胞对BCR信号应答的关键分子。在缺乏Ikaros的情况下, 滤泡B细胞经抗免疫球蛋白M (immunoglobulin M, IgM) 刺激后会快速增殖, 同时可以检测到BCR下游丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK) 通路的异常活化^{[65, 66]}。Ikaros作为B1细胞发育与功能的关键负调控因子, 其缺失会导致B1细胞稳态失衡。Ikaros缺陷小鼠脾脏和骨髓中B1细胞数量显著增加, 并且在Toll样受体4 (Toll-like receptor 4, TLR4) 刺激下的B1细胞呈高反应性, 分泌大量IgM^[67]。

2.2　Ikaros家族蛋白与先天免疫

在先天性淋巴细胞方面, 如前所述, 度胺药物可以通过抑制Aiolos和Ikaros阻碍ILC3向ILC1/NK细胞的转分化^[36]。Aiolos还可以通过抑制程序性细胞死亡蛋白1 (programmed cell death protein 1, PD-1) 来支持IL-5的产生和ST2⁺ ILC2s的增殖, 从而促进嗜酸性粒细胞募集, 最终正向调节2型先天免疫应答^[68]。

在嗜酸性粒细胞中, Aiolos能够促进这些细胞从血液循环中脱离, 并迁移至黏膜组织。Aiolos的缺失会显著削弱通过C-C基序趋化因子配体11 (C-C motif chemokine ligand 11, CCL11)/CC趋化因子受体3 (C-C chemokine receptor type 3, CCR3) 信号轴介导的细胞外信号调节激酶1/2 (extracellular signal-regulated kinase 1/2, ERK1/2) 活化和肌动蛋白聚合, 进而破坏细胞迁移能力^[69]。

在NK细胞方面, Ikaros和Aiolos与AP-1家族成员结合对NK细胞发育至关重要。研究表明, 同时敲除NK细胞中的Ikaros和Aiolos会降低AP-1的核心组成部分Jun/Fos (Fos proto-oncogene) 表达, 并导致外周NK细胞完全缺失^[70]。

Ikaros对人类树突状细胞(dendritic cell, DC) 的发育和功能具有调控作用。Ikaros与活化的Notch信号通路协作, 维持单核-树突状细胞祖细胞(monocyte and dendritic progenitors, MDPs) 和共同树突状细胞祖细胞(common dendritic progenitors, CDPs) 的稳态, 而从CDP向浆细胞样树突状细胞(plasmacytoid dendritic cell, pDC) 的分化需要Ikaros拮抗转化生长因子β (transforming growth factor beta, TGF-β) 的功能^[71]。Ikaros缺乏会降低pDC和非经典单核细胞数量, 增加Ⅰ型经典树突状细胞(conventional dendritic cell 1, cDC1) 的数量。此外, Ikaros缺乏患者DC和单核细胞分泌的IFNα、肿瘤坏死因子(tumor necrosis factor, TNF) 和IL-12减少^[72]。

在CD34⁺细胞中, 转录因子PU.1对中性粒细胞的发育成熟至关重要, 而Ikaros可能是PU.1的上游调控因子。Ikaros的缺失导致PU.1表达下调, 该机制可部分阐释使用度胺类药物治疗中继发中性粒细胞减少症的原因^[73]。另有研究发现, Ikaros和MYB蛋白(MYB pro-oncogene, Myb) 形成复合物靶向IRF8基因并诱导一个长链非编码RNA (IRF8-2) 的表达。该长链非编码RNA协同ZFP36无名指蛋白样1 (ZFP36 ring finger protein like 1, Zfp36l1) 蛋白稳定结合IRF8的mRNA, 达到转录后抑制IRF8表达的效果, 从而促进中性粒细胞定向分化^[74]。

在使用度胺类药物治疗MM的过程中, 有研究认为肿瘤微环境中巨噬细胞的Ikaros水平下降, 通过下调IRF4并上调IRF5的表达, 导致巨噬细胞从M2样表型向肿瘤毒性的M1样表型转变^{[75, 76]}。

2.3　Ikaros家族蛋白与细胞的信号应答

Ikaros在小鼠巨噬细胞脂多糖应答基因的调控中表现出抑制与提升双重调控功能: 其既抑制部分早期炎症基因, 又通过维持NF-κB结合和调控染色质可及性, 激活中晚期免疫应答基因。研究人员认为该项成果支持以往关于Ikaros调控机制的设想, 即Ikaros发挥转录抑制或激活作用, 取决于其自身表达水平的精准调控^[77]。

在DC中的研究认为Ikaros作为关键转录因子可增强促炎因子的产生及抗原呈递功能, 进而促进炎症反应。在免疫球蛋白A肾病的动物模型中, 降低Ikaros水平可以缓解肾脏损伤^[78]。

在成熟T细胞中, Ikaros调控炎症细胞因子基因表达以及Ⅰ型干扰素诱导的基因程序变化水平^[44]。类风湿关节炎和银屑病关节炎患者T细胞中的Ikaros表达降低, 导致花生四烯酸调控的钙选择性通道活性增强, 致使细胞反应性增高, 从而促进了慢性炎症过程^[79]。

2.4　Ikaros家族蛋白与细胞的代谢

有研究显示PAX5和Ikaros共同作用, 转录调控糖皮质激素受体NR3C1 (nuclear receptor subfamily 3 group C member 1)、硫氧还蛋白相互作用蛋白(thioredoxin-interacting protein, TXNIP)、大麻素受体2 (cannabinoid receptor 2, CNR2) 等核心因子, 限制B淋巴细胞的糖与能量供给, 迫使细胞处于慢性能量匮乏状态, 导致能量应激传感器AMP活化蛋白激酶(AMP-activated protein kinase, AMPK) 的持续性激活, 可能有助于抑制细胞癌变^[80]。类似的糖代谢变化在整合素失活的DC细胞中也有报道^[81]。HIV感染者的单核细胞来源的巨噬细胞表现出一种特定的代谢适应。研究认为, 这种适应涉及Ikaros/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR) 依赖性的线粒体呼吸和糖酵解增加, 下调Ikaros和mTOR可以纠正该代谢状态^[82]。

2.5　Ikaros家族蛋白与神经系统的发育分化

Helios参与调控纹状体-苍白球中神经元亚群的发育过程。Helios在神经祖细胞中表达, 可使细胞周期停滞于G1/G0期。Helios缺失则会导致神经祖细胞进入S期的比例增加且S期延长, 进而损害纹状体神经的生成^[83]。

在早期针对小鼠视网膜发育的研究中发现, Ikaros调控除视锥光感受器以外早期生成细胞类型的产生。近期研究认为, 在视锥光感受器的生成过程中, Eos能够结合并抑制参与晚期杆状光感受器分化的基因, 从而促进视锥细胞生成。另外, 在此过程中Eos与Ikaros展现出协同调控的作用。在视网膜发育晚期, 当祖细胞不再表达Ikaros时, Eos则定位至生成胶质细胞的靶基因, 参与调控米勒胶质细胞的生成^[84]。

一项关于耳蜗细胞的研究发现, 无调性bHLH转录因子1 (atonal bHLH transcription factor 1, ATOH1) 和Helios双重表达可将成年小鼠耳蜗支持细胞在体内转化为表达马达蛋白prestin的外毛细胞样细胞^[85]。

2.6　Ikaros家族蛋白与病毒的相互作用

一项临床研究显示EB病毒(Epstein-Barr virus, EBV) 载量与活动期溃疡性结肠炎患者Helios⁺Foxp3⁺ Treg数量负相关^[86]。另一项研究发现, Ikaros参与抑制EBV关键致癌蛋白潜伏膜蛋白1 (latent membrane protein 1, LMP1) 的表达。同时突变LMP1启动子区中增强子盒和Ikaros蛋白结合区域可导致LMP1表达上升, 并使被感染的B细胞趋于永生。然而, 单独突变其中任何一个位点, 对LMP1表达的影响均有限^[87]。另外, EBV的BamHI-A右向转录本(BamHI-A rightward transcripts, BART) 长链非编码RNA对Aiolos具有诱导表达作用。敲低BART长链非编码RNA后, C666-1鼻咽癌细胞中Aiolos表达下调^[88]。

人类T细胞白血病病毒1型(human T-lymphotropic virus type 1, HTLV-1) 是首个被发现能直接导致人类癌症的逆转录病毒。在多数HTLV-1感染的T细胞系中, Eos蛋白呈高表达。进一步研究发现, 病毒蛋白X区反式激活因子(trans-activator X, Tax) 的诱导表达能显著上调Eos的表达, 且二者之间存在物理相互作用^[89]。

上述研究涉及的Ikaros家族蛋白调控网络详见图 2。

2.7　疾病相关的Ikaros家族蛋白突变

近些年, 在患者体内发现多种Ikaros家族蛋白突变, 相关疾病主要涉及原发性免疫缺陷病、自身免疫性疾病、恶性肿瘤和炎症(表 2)^[90-109]。许多突变发生在N端锌指区, 研究结果多认为突变破坏了蛋白结合靶基因位点的能力, 导致对下游基因调控失败^[90-106]。在C端锌指区的直接突变相对较少, 但部分突变会导致蛋白质翻译提前终止或编码阅读框移位, 导致C端锌指结构域完全丢失或者翻译产物错误^{[91, 96]}。这些突变首先可以影响Ikaros家族蛋白的二聚或者多聚功能, 其次可能对蛋白稳定性产生影响。N端锌指区到N末端之间区域被认为同样可能影响蛋白稳定性^{[91, 104, 107]}。在两个锌指区之间序列中也发现了突变, 既往研究认为该区域具有招募表观遗传修饰复合物的功能^{[91, 96, 104, 107-109]}。

3　Ikaros家族蛋白的相关调控

收起

3.1　Ikaros转录调控机制

在早期研究中, 转录调控机制已经取得诸多成果, 相关发现主要围绕RNA聚合酶及表观遗传调控两方面。感兴趣的读者可以参考既往的综述文章^[1]。近些年, 表观调控领域相关研究不断深化, 同时在基因组空间构建方面取得重要突破。

在B-ALL中, Ikaros可通过两种不同的机制诱导抑制性染色质的形成, 抑制其下游靶基因的转录: 一是Ikaros直接结合导致异染色质的形成, 表现为H3K9me3增加和H3K9ac减少; 二是招募组蛋白去乙酰化酶1 (histone deacetylase 1, HDAC1), 在H3K9ac减少的同时表现出H3K27me3水平的显著提升^[110]。在白血病细胞中, Ikaros与HDAC1协同抑制组蛋白去甲基化酶含Jumonji/ARID结构域蛋白1B (Jumonji/ARID domain-containing protein 1B, JARID1B) 的表达, 导致全基因组H3K4me3水平升高。CK2可破坏此调控通路, 而抑制CK2则可恢复Ikaros-HDAC1对JARID1B启动子的结合, 同时伴随H3K27me3水平升高与H3K9ac水平降低, 重建转录抑制, 诱导白血病细胞生长停滞^[111]。此外, Ikaros还通过与共调控因子协同作用来实现转录抑制功能, 如CRBN^[112]与C端结合蛋白(C-terminal binding protein, CtBP)^[113]。

另一方面, Ikaros亦具备转录激活功能。在肝细胞癌细胞中, Ikaros可结合锌-α2-糖蛋白基因(zinc-alpha-2-glycoprotein gene, AZGP1) 启动子并上调其表达; 同时, Ikaros与组蛋白H4乙酰化形成正反馈调节环路, 协同调控AZGP1的表达^[114]。

研究发现, Ikaros对基因组空间结构进行组织谱系特异性组装。在前B细胞中, 通过结合大量淋系增强子, 由Ikaros介导的染色质环可以提升下游基因活性或者帮助未活化基因进入待激发状态。同时, 这些染色质环可以突破由基因组结构基础构建因子CCCTC结合因子(CCCTC-binding factor, CTCF) 所界定的拓扑结构域(topologically associating domain, TAD) 边界, 在稳定的TAD骨架基础之上构建谱系特异性的调控单元^[115]。这项研究凸显了Ikaros二聚或者多聚化功能的重要性。在Ikaros聚合体中, 各个Ikaros分子均携带DNA结合模块, 可使基因组上不同的位点聚合。在Ikaros复合物自身或基因组结构基础构建因子黏连蛋白(cohesin) 的协同作用下, 拉近两个基因位点的空间距离, 形成染色质环。

3.2　Ikaros所受到的调控

3.2.1　基因表达及蛋白稳定性

Ikaros的功能受到非编码元件的调控。非编码元件Daedalus基因位点的缺失导致Ikaros异构体表达改变及其蛋白水平显著下降, 这一调控作用可能通过直接的DNA相互作用实现。红系-淋系分化检查点受Ikaros调控, 而Daedalus能在淋巴系细胞中特异性稳定Ikaros活性, 其缺失则促使细胞向红系转换^[116]。位于IKZF1基因上游120 kb处的E120增强子是另一个关键调控元件, 删除该增强子会导致IKZF1 mRNA水平显著下降^[117]。

Ikaros蛋白的稳定性受其近N端区域与C端二聚化结构域的调控, 已鉴定的相关突变体包括D22N、V52L、Y503^*。近N端区第1~116位氨基酸序列被定义为蛋白稳定性关联区域, 研究认为该区域的变异会导致蛋白稳定性降低。此外, 破坏二聚化结构域会干扰Ikaros的SUMO化(SUMOylation), 进而影响其蛋白的稳定性^[118]。

3.2.2　翻译后修饰

对蛋白进行修饰的酶常可作为药物作用靶点。近年研究又鉴定出多种Ikaros家族蛋白的翻译后修饰类型。

3.2.2.1　SUMO化与泛素化

在T细胞核内, Ikaros可发生SUMO化修饰, 其3个赖氨酸残基(K58、K240和K425) 上可形成包含小泛素样修饰蛋白1 (small ubiquitin-like modifier 1, SUMO1) 和/或SUMO2/3的多种类型修饰。SUMO化的Ikaros抑制小鼠白血病细胞扩增的能力减弱。此外, 在人类B-ALL细胞中可检测到Ikaros呈现高水平SUMO化修饰, 而该修饰在健康人外周血白细胞中未检测到。上述结果提示, SUMO化修饰可能弱化Ikaros的肿瘤抑制功能^[119]。

在急性髓系白血病(acute myeloid leukemia, AML) 细胞中, 热休克蛋白90 (heat shock protein 90, Hsp90) 是维持Ikaros蛋白稳定性的关键调控因子, 使用Hsp90抑制剂STA9090可诱导Ikaros经泛素-蛋白酶体通路降解。该降解过程需要C端HSC70结合蛋白(C-terminal HSC70 binding protein, CHIP) 与Ikaros相互作用, 但是CHIP的E3连接酶结构域并非必需, 提示可能还存在其他E3连接酶协同参与Ikaros的降解^[120]。

3.2.2.2　磷酸化

磷酸化修饰在Ikaros功能调控中同样发挥关键作用, 多项研究聚焦于CK2激酶。CK2激酶可磷酸化Ikaros的多个位点, 进而影响其DNA结合能力、亚细胞定位及蛋白稳定性, 干扰其对下游基因的转录活性^[121-123]。CK2与Akt共同参与低剂量电离辐射诱导的Ikaros (S391/S393位点) 磷酸化, 由此影响Ikaros对G1/S期细胞周期进程的调控能力^[124]。在B-ALL中, 存在一个由CK2、蛋白磷酸酶1 (protein phosphatase 1, PP1)、Ikaros和Ras相关蛋白Rab-20 (Ras-related protein Rab-20) 构成的调控网络。具体而言, CK2激酶通过磷酸化Ikaros, 削弱其与DNA的结合能力, 从而解除对Rab20启动子的抑制; 相反, PP1通过对Ikaros去磷酸化, 强化对Rab20的转录抑制。此调控模式维持着精细的信号平衡, 其失调可能导致Rab20异常表达, 进而推动白血病进展^[125]。

糖原合成酶激酶3β (glycogen synthase kinase 3 β, GSK3β) 可与Ikaros相互作用并磷酸化其Ser391位点。Ikaros Ser391D突变蛋白(模拟391位点磷酸化) 与膜联蛋白A4 (annexin A4, ANXA4) 启动子的结合力增强, 进而抑制ANXA4表达, 导致高糖条件下成纤维细胞迁移能力的提升^[126]。BCR信号通路关键激酶布鲁顿酪氨酸激酶(Bruton's tyrosine kinase, BTK) 的活化, 可磷酸化Ikaros的特定丝氨酸残基(Ser214/215/442/445), 诱导Ikaros发生核转位并发挥其转录活性, 从而抑制YES原癌基因1 (YES proto-oncogene 1, YES1) 表达并促进MYC表达^[127]。此外, 在有丝分裂过程中, Ikaros与Aiolos需依赖PDZ结合激酶(PDZ-binding kinase, PBK) 介导的磷酸化方可从染色体上解离^[128]。

3.2.2.3　乳酸化

Ⅵ型胶原蛋白α1链(collagen type Ⅵ alpha 1 chain, COL6A1) 激活黏着斑激酶(focal adhesion kinase, FAK)/原癌基因酪氨酸蛋白激酶Src (proto-oncogene tyrosine-protein kinase Src, SRC)/河马信号通路(Hippo signaling pathway, Hippo)/Yes相关蛋白(Yes-associated protein, YAP) 信号轴, 促进了Ikaros在第255位赖氨酸处的乳酸化修饰。乳酸化的Ikaros易位至细胞核, 增强泛素样修饰蛋白D (ubiquitin-like modifier D, UBD) 转录。UBD辅助降解紧密连接蛋白5, 进而促进内皮屏障破坏和单核细胞浸润^[129]。另外, 有研究认为乳酸化的Ikaros可能成为类风湿关节炎早期诊断及疾病活动度评估的潜在生物标志物^[130]。

4　讨论与展望

收起

近年来, Ikaros家族相关研究成果不断涌现, 这在一定程度上得益于度胺类药物突出的临床应用价值。

在Ikaros的生理功能研究领域, Treg方向是目前颇受关注的研究热点, 几乎所有Ikaros家族蛋白都在Treg细胞中发挥作用。然而, 体内与体外研究结果经常不一致, 导致一些争论的产生。尽管如此, 度胺类药物已在系统性红斑狼疮等自身免疫性疾病中开展了应用尝试。后续研究或许可以考虑Ikaros蛋白家族在Treg细胞上的集合作用, 而不是针对单一成分。

Ikaros家族转录因子对下游基因的调控代表着一类极端复杂的模式。其C端锌指结构域可介导家族多种异构体蛋白之间的聚合, 从而产生大量可能的复合物形式。这些复合物携带不同种类和不同数量的N端锌指, 可以不同形式结合到下游多种DNA位点上, 进而影响基因表达。当把这种复杂聚合模式与蛋白功能联系到一起, 即Ikaros家族成员内部存在功能上相互制约与冗余重叠的现象, 或许提示功能的表象是这些聚合物综合作用的结果, 应该将整个家族作为一个整体进行研究。

Ikaros在调节基因组空间结构上的作用可以解释诸多复杂的生物学现象。大量下游基因的表达调控, 本质上源于这些基因在空间上的组织方式。Ikaros DNA结合能力的损伤可能破坏由Ikaros二聚或多聚复合物联系的两个远距离基因位点的聚合。同时, 无DNA结合功能的蛋白会对功能性蛋白产生负面作用, 从而干扰染色质环的形成。当Ikaros家族蛋白过表达, 有效结合两个或多个DNA位点的蛋白复合物增多, 可能通过形成特异性相对较弱的染色质环来干扰下游基因表达。Ikaros通常在超级增强子附近形成染色质环, 由此拉近许多基因与增强子之间的空间距离, 同时物理隔离一些基因与增强子的接触, 于是解释了研究人员曾经非常疑惑的Ikaros家族转录因子既展现激活作用又具备抑制作用的现象。随着Ikaros家族在基因组空间结构上功能的确定, 了解其在基因组上的组织架构规律, 将对深入理解染色质环对下游基因调控作用机制并且更加精细地完成对相关生理功能的扰动提供帮助, 进一步推动靶向Ikaros家族药物的发展。

综上所述, Ikaros家族蛋白已经成为药物研发的热点, 随着其作用机制的逐步明晰及新型靶向药物的持续开发, 针对Ikaros的治疗策略正朝着更高效、更精准的方向演进。新发现的非经典功能、突变相关疾病、调控机制, 则为下一阶段的靶向策略提供了更大空间。Ikaros家族蛋白的功能仍需继续探索, 每一个新机制的揭示, 都可能对应新的治疗窗口。正因如此, 以Ikaros家族蛋白作为靶点的研究更值得关注。

参考文献

收起

文献

收起

参考文献引证文献

排序方式：

Fan Y, Lu D. The Ikaros family of zinc-finger proteins [J]. Acta Pharm Sin B, 2016, 6: 513-521.

Wang Y, Long J, Chang Q, et al. The application of small molecule PROTAC in researches of different targets [J]. Acta Pharm Sin (药学学报), 2020, 55: 446-452.

Fischer ES, Böhm K, Lydeard JR, et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide [J]. Nature, 2014, 512: 49-53.

Petzold G, Fischer ES, Thomä NH. Structural basis of lenalidomide-induced CK1alpha degradation by the CRL4(CRBN) ubiquitin ligase [J]. Nature, 2016, 532: 127-130.

Chamberlain PP, Lopez-Girona A, Miller K, et al. Structure of the human cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs [J]. Nat Struct Mol Biol, 2014, 21: 803-809.

Díaz T, Rodríguez V, Lozano E, et al. The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling [J]. Haematologica, 2017, 102: 1776-1784.

Fuchs O. Targeting cereblon in hematologic malignancies [J]. Blood Rev, 2023, 57: 100994.

Watson ER, Novick S, Matyskiela ME, et al. Molecular glue CELMoD compounds are regulators of cereblon conformation [J]. Science, 2022, 378: 549-553.

Tang C, Li Z, Lu R, et al. Discovery of a dual-target CRBN-mediated degrader for IKZF1/3 and GSPT1 proteins [J]. Bioorg Chem, 2026, 169: 109367.

Gemechu Y, Millrine D, Hashimoto S, et al. Humanized cereblon mice revealed two distinct therapeutic pathways of immunomodulatory drugs [J]. Proc Natl Acad Sci U S A, 2018, 115: 11802-11807.

Li P, Hu X, Fan Z, et al. Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation [J]. J Hematol Oncol, 2024, 17: 77.

Wei T, Sun S, Hu X, et al. Discovery of novel potent triple IKZF1/2/3 degraders for the treatment of hematological cancers [J]. J Med Chem, 2025, 68: 16237-16259.

Montoya S, Bourcier J, Noviski M, et al. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127 [J]. Science, 2024, 383: eadi5798.

Weiss MM, Zheng X, Ji N, et al. Discovery of KT-413, a targeted protein degrader of IRAK4 and IMiD substrates targeting MYD88 mutant diffuse large B-cell lymphoma [J]. J Med Chem, 2024, 67: 10548-10566.

Sievers QL, Petzold G, Bunker RD, et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN [J]. Science, 2018, 362: eaat0572.

Brennan PJ, Saunders RE, Spanou M, et al. Orthogonal IMiD-degron pairs induce selective protein degradation in cells [J]. ACS Chem Biol, 2025, 20: 2827-2843.

Lonial S, Popat R, Hulin C, et al. Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): A multicentre, multicohort, open-label, phase 1/2 trial [J]. Lancet Haematol, 2022, 9: e822-e832.

Zhang X, Dhruv H, Deng Q, et al. Discovery of a novel series of iso-indolinone-based glutarimides as highly efficacious and selective IKZF2 molecular glue degraders [J]. J Med Chem, 2025, 68: 18230-18257.

Zhang X, Deng Q, Dhruv H, et al. Overcoming CK1alpha liability in the discovery of a series of isoindolinone glutarimides as selective IKZF2 molecular glue degraders [J]. Bioorg Med Chem Lett, 2025, 124: 130263.

Chen Z, Dhruv H, Zhang X, et al. Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy [J]. Nat Commun, 2025, 16: 4095.

Bonazzi S, d'Hennezel E, Beckwith REJ, et al. Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy [J]. Cell Chem Biol, 2023, 30: 235-247. e12.

Harama D, Yahata T, Kagami K, et al. IMiDs uniquely synergize with TKIs to upregulate apoptosis of Philadelphia chromosome-positive acute lymphoblastic leukemia cells expressing a dominant-negative IKZF1 isoform [J]. Cell Death Discov, 2021, 7: 139.

Zeidner JF, Knaus HA, Zeidan AM, et al. Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS [J]. Leukemia, 2020, 34: 1563-1576.

Dou A, Fang J. Cyclosporine broadens the therapeutic potential of lenalidomide in myeloid malignancies [J]. J Cell Immunol, 2020, 2: 237-244.

Jin Y, Liao X, Zhang J, et al. Modular PROTAC/IMiD bifunctional molecule design for the degradation of synergistic targets in the treatment of lymphoma [J]. J Med Chem, 2025, 68: 21249-21281.

Verano AL, You I, Donovan KA, et al. Redirecting the neo-substrate specificity of cereblon-targeting PROTACs to Helios [J]. ACS Chem Biol, 2022, 17: 2404-2410.

Wang Z, Zhou G, Risu N, et al. Lenalidomide enhances CAR-T cell activity against solid tumor cells [J]. Cell Transplant, 2020, 29: 963689720920825.

Bird S, Pawlyn C. IMiD resistance in multiple myeloma: Current understanding of the underpinning biology and clinical impact [J]. Blood, 2023, 142: 131-140.

D'Souza C, Prince HM, Neeson PJ. Understanding the role of T-cells in the antimyeloma effect of immunomodulatory drugs [J]. Front Immunol, 2021, 12: 632399.

Ishibashi M, Yamamoto J, Ito T, et al. Durvalumab combined with immunomodulatory drugs (IMiD) overcomes suppression of antitumor responses due to IMiD-induced PD-L1 upregulation on myeloma cells [J]. Mol Cancer Ther, 2021, 20: 1283-1294.

Röhner L, Ng YLD, Scheffold A, et al. Generation of a lenalidomide-sensitive syngeneic murine in vivo multiple myeloma model by expression of Crbn^I391V [J]. Exp Hematol, 2021, 93: 61-69. e4.

Lu G, Weng S, Matyskiela M, et al. UBE2G1 governs the destruction of cereblon neomorphic substrates [J]. Elife, 2018, 7: e40958.

Zhou N, Gutierrez-Uzquiza A, Zheng XY, et al. RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation [J]. Leukemia, 2019, 33: 2006-2021.

Wu W, Nelson GM, Koch R, et al. Overcoming IMiD resistance in T-cell lymphomas through potent degradation of ZFP91 and IKZF1 [J]. Blood, 2022, 139: 2024-2037.

Werth VP, Merrill JT, Furie R, et al. Effect of iberdomide on cutaneous manifestations in systemic lupus erythematosus: A randomized phase 2 clinical trial [J]. J Am Acad Dermatol, 2025, 92: 435-443.

Mazzurana L, Forkel M, Rao A, et al. Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3-ILC1/NK cell transdifferentiation [J]. Eur J Immunol, 2019, 49: 1344-1355.

Ne E, Crespo R, Izquierdo-Lara R, et al. Catchet-MS identifies IKZF1-targeting thalidomide analogues as novel HIV-1 latency reversal agents [J]. Nucleic Acids Res, 2022, 50: 5577-5598.

Dulmovits BM, Appiah-Kubi AO, Papoin J, et al. Pomalidomide reverses gamma-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors [J]. Blood, 2016, 127: 1481-1492.

Georgopoulos K, Moore DD, Derfler B. Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment [J]. Science, 1992, 258: 808-812.

Huang Y, Lu Y, He Y, et al. Ikzf1 regulates embryonic T lymphopoiesis via Ccr9 and Irf4 in zebrafish [J]. J Biol Chem, 2019, 294: 16152-16163.

Agnihotri P, Robertson NM, Umetsu SE, et al. Lack of Ikaros cripples expression of Foxo1 and its targets in naive T cells [J]. Immunology, 2017, 152: 494-506.

Stoddard J, Kuehn HS, Tagirasa R, et al. IKAROS regulates human T cell phenotype at a thymic and postthymic level [J]. JCI Insight, 2025, 10: e197359.

Powell MD, Read KA, Sreekumar BK, et al. Ikaros zinc finger transcription factors: Regulators of cytokine signaling pathways and CD4⁺ T helper cell differentiation [J]. Front Immunol, 2019, 10: 1299.

Lyon de Ana C, Arakcheeva K, Agnihotri P, et al. Lack of Ikaros deregulates inflammatory gene programs in T cells [J]. J Immunol, 2019, 202: 1112-1123.

Thomas RM, Pahl MC, Wang L, et al. Foxp3 depends on Ikaros for control of regulatory T cell gene expression and function [J]. Elife, 2024, 12: RP91392.

Ng MSF, Roth TL, Mendoza VF, et al. Helios enhances the preferential differentiation of human fetal CD4⁺ naive T cells into regulatory T cells [J]. Sci Immunol, 2019, 4: eaav5947.

Lam AJ, Uday P, Gillies JK, et al. Helios is a marker, not a driver, of human Treg stability [J]. Eur J Immunol, 2022, 52: 75-84.

Gokhale AS, Gangaplara A, Lopez-Occasio M, et al. Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity [J]. J Autoimmun, 2019, 105: 102300.

Xin Y, Yang M, Zhao Z, et al. AIM2 deficiency in CD4⁺ T cells promotes psoriasis-like inflammation by regulating Th17-Treg axis via AIM2-IKZF2 pathway [J]. J Autoimmun, 2025, 150: 103351.

Read KA, Powell MD, Baker CE, et al. Integrated STAT3 and Ikaros zinc finger transcription factor activities regulate Bcl-6 expression in CD4⁺ Th cells [J]. J Immunol, 2017, 199: 2377-2387.

Pokhrel S, Dileepan G, Leonard MR, et al. Aiolos restricts the generation of antigen-inexperienced, virtual memory CD8⁺ T cells in mice [J]. Nat Commun, 2025, 17: 839.

Jones DM, Tuazon JA, Read KA, et al. Cytotoxic programming of CD4⁺ T cells is regulated by opposing actions of the related transcription factors Eos and Aiolos [J]. J Immunol, 2024, 212: 1129-1141.

Leonard MR, Jones DM, Read KA, et al. Aiolos promotes CXCR3 expression on Th1 cells via positive regulation of IFN-gamma/STAT1 signaling [J]. JCI Insight, 2024, 10: e180287.

Gowda C, Soliman M, Kapadia M, et al. Casein kinase Ⅱ (CK2), glycogen synthase kinase-3 (GSK-3) and Ikaros mediated regulation of leukemia [J]. Adv Biol Regul, 2017, 65: 16-25.

Dovat E, Song C, Hu T, et al. Transcriptional regulation of PIK3CD and PIKFYVE in T-cell acute lymphoblastic leukemia by IKAROS and protein kinase CK2 [J]. Int J Mol Sci, 2021, 22: 819.

Yuan T, Yang Y, Chen J, et al. Regulation of PI3K signaling in T-cell acute lymphoblastic leukemia: A novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD [J]. Leukemia, 2017, 31: 2355-2364.

Zhen J, Yuan J, Fu Y, et al. IL-22 promotes Fas expression in oligodendrocytes and inhibits FOXP3 expression in T cells by activating the NF-kappaB pathway in multiple sclerosis [J]. Mol Immunol, 2017, 82: 84-93.

Han J, Jin R, Zhang M, et al. Ikaros 6 protects acute lymphoblastic leukemia cells against daunorubicin-induced apoptosis by activating the Akt-FoxO1 pathway [J]. J Leukoc Biol, 2017, 101: 675-681.

Hu Y, Zhang Z, Kashiwagi M, et al. Superenhancer reprogramming drives a B-cell-epithelial transition and high-risk leukemia [J]. Genes Dev, 2016, 30: 1971-1990.

Heizmann B, Le Gras S, Simand C, et al. Ikaros antagonizes DNA binding by STAT5 in pre-B cells [J]. PLoS One, 2020, 15: e0242211.

Katerndahl CDS, Heltemes-Harris LM, Willette MJL, et al. Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival [J]. Nat Immunol, 2017, 18: 694-704.

Fedl AS, Tagoh H, Gruenbacher S, et al. Transcriptional function of E2A, Ebf1, Pax5, Ikaros and Aiolos analyzed by in vivo acute protein degradation in early B cell development [J]. Nat Immunol, 2024, 25: 1663-1677.

Hu Y, Yoshida T, Georgopoulos K. Transcriptional circuits in B cell transformation [J]. Curr Opin Hematol, 2017, 24: 345-352.

Ochiai K, Kondo H, Okamura Y, et al. Zinc finger-IRF composite elements bound by Ikaros/IRF4 complexes function as gene repression in plasma cell [J]. Blood Adv, 2018, 2: 883-894.

Heizmann B, Sellars M, Macias-Garcia A, et al. Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways [J]. Biochem Biophys Res Commun, 2016, 470: 714-720.

Oliveira VC, Lacerda MP, Moraes BBM, et al. Deregulation of Ikaros expression in B-1 cells: New insights in the malignant transformation to chronic lymphocytic leukemia [J]. J Leukoc Biol, 2019, 106: 581-594.

Macias-Garcia A, Heizmann B, Sellars M, et al. Ikaros is a negative regulator of B1 cell development and function [J]. J Biol Chem, 2016, 291: 9073-9086.

Qiu J, Zhang J, Ji Y, et al. Tissue signals imprint Aiolos expression in ILC2s to modulate type 2 immunity [J]. Mucosal Immunol, 2021, 14: 1306-1322.

Zaini A, Zaph C. Aiolos: A molecular guardian of type 2 innate immune cell residency and response [J]. Mucosal Immunol, 2021, 14: 1221-1223.

Goh W, Sudholz H, Foroutan M, et al. IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development [J]. Nat Immunol, 2024, 25: 240-255.

Mastio J, Simand C, Cova G, et al. Ikaros cooperates with Notch activation and antagonizes TGFbeta signaling to promote pDC development [J]. PLoS Genet, 2018, 14: e1007485.

Cytlak U, Resteu A, Bogaert D, et al. Ikaros family zinc finger 1 regulates dendritic cell development and function in humans [J]. Nat Commun, 2018, 9: 1239.

Li S, Fu J, Wang H, et al. IMiD compounds affect CD34⁺ cell fate and maturation via CRBN-induced IKZF1 degradation [J]. Blood Adv, 2018, 2: 492-504.

He Y, Li Y, Shao Y, et al. Regulation of an lncRNA irf8 by the Ikzf1/Myb complex drives neutrophil development [J]. Proc Natl Acad Sci U S A, 2025, 122: e2502741122.

De Sanctis F, Bronte V. How to reprogram myeloma-associated macrophages: Target IKZF1 [J]. Cancer Immunol Res, 2021, 9: 254.

Mougiakakos D, Bach C, Böttcher M, et al. The IKZF1-IRF4/IRF5 axis controls polarization of myeloma-associated macrophages [J]. Cancer Immunol Res, 2021, 9: 265-278.

Oh KS, Gottschalk RA, Lounsbury NW, et al. Dual roles for Ikaros in regulation of macrophage chromatin state and inflammatory gene expression [J]. J Immunol, 2018, 201: 757-771.

Peng F, Sheng C, He J, et al. IKZF1 as a potential therapeutic target for dendritic cell-mediated immunotherapy in IgA nephropathy [J]. Cell Commun Signal, 2025, 23: 216.

Ye Z, Shen Y, Jin K, et al. Arachidonic acid-regulated calcium signaling in T cells from patients with rheumatoid arthritis promotes synovial inflammation [J]. Nat Commun, 2021, 12: 907.

Chan LN, Chen Z, Braas D, et al. Metabolic gatekeeper function of B-lymphoid transcription factors [J]. Nature, 2017, 542: 479-483.

Harjunpää H, Somermäki R, Saldo Rubio G, et al. Loss of beta2-integrin function results in metabolic reprogramming of dendritic cells, leading to increased dendritic cell functionality and anti-tumor responses [J]. Oncoimmunology, 2024, 13: 2369373.

Vittori C, Faia C, Wyczechowska D, et al. IKAROS expression drives the aberrant metabolic phenotype of macrophages in chronic HIV infection [J]. Clin Immunol, 2024, 260: 109915.

Martín-Ibáñez R, Pardo M, Giralt A, et al. Helios expression coordinates the development of a subset of striatopallidal medium spiny neurons [J]. Development, 2017, 144: 1566-1577.

Javed A, Santos-França PL, Mattar P, et al. Ikaros family proteins redundantly regulate temporal patterning in the developing mouse retina [J]. Development, 2023, 150: dev200436.

Sun S, Li S, Luo Z, et al. Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells [J]. Elife, 2021, 10: e66547.

Long Y, Zhao X, Xia C, et al. Infection of Epstein-Barr virus is associated with the decrease of Helios⁺FoxP3⁺ regulatory T cells in active ulcerative colitis patients [J]. Immunol Invest, 2021, 50: 23-36.

Yoshida M, Murata T, Ashio K, et al. Characterization of a suppressive cis-acting element in the Epstein-Barr virus LMP1 promoter [J]. Front Microbiol, 2017, 8: 2302.

Verhoeven RJA, Tong S, Mok BW, et al. Epstein-Barr virus BART long non-coding RNAs function as epigenetic modulators in nasopharyngeal carcinoma [J]. Front Oncol, 2019, 9: 1120.

Naito T, Ushirogawa H, Fukushima T, et al. EOS, an Ikaros family zinc finger transcription factor, interacts with the HTLV-1 oncoprotein Tax and is downregulated in peripheral blood mononuclear cells of HTLV-1-infected individuals, irrespective of clinical statuses [J]. Virol J, 2019, 16: 160.

Kuehn HS, Boast B, Rosenzweig SD. Inborn errors of human IKAROS: LOF and GOF variants associated with primary immunodeficiency [J]. Clin Exp Immunol, 2023, 212: 129-136.

Kuehn HS, Nunes-Santos CJ, Rosenzweig SD. IKAROS-associated diseases in 2020: Genotypes, phenotypes, and outcomes in primary immune deficiency/inborn errors of immunity [J]. J Clin Immunol, 2021, 41: 1-10.

Guess R, Harocopos G, Bednarski JJ, et al. Pediatric necrobiotic xanthogranuloma as a novel phenotype of IKAROS gain of function [J]. J Clin Immunol, 2023, 44: 19.

Boutboul D, Kuehn HS, van de Wyngaert Z, et al. Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency [J]. J Clin Invest, 2018, 128: 3071-3087.

Hetemäki I, Kaustio M, Kinnunen M, et al. Loss-of-function mutation in IKZF2 leads to immunodeficiency with dysregulated germinal center reactions and reduction of MAIT cells [J]. Sci Immunol, 2021, 6: eabe3454.

Shi X, Cao X, Huang M, et al. Identification and functional analysis of a de novo IKZF3 mutation in a pediatric patient with combined immunodeficiency [J]. J Clin Immunol, 2024, 44: 117.

Kuehn HS, Niemela JE, Stoddard J, et al. Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies [J]. Blood, 2021, 137: 349-363.

Boast B, Miosge LA, Kuehn HS, et al. A point mutation in IKAROS ZF1 causes a B cell deficiency in mice [J]. J Immunol, 2021, 206: 1505-1514.

Kuehn HS, Nunes-Santos CJ, Rosenzweig SD. Germline IKZF1 mutations and their impact on immunity: IKAROS-associated diseases and pathophysiology [J]. Expert Rev Clin Immunol, 2021, 17: 407-416.

Díaz-Alberola I, Espuch-Oliver A, García-Aznar JM, et al. Common variable immunodeficiency associated with a de novo IKZF1 variant and a low humoral immune response to the SARS-CoV-2 vaccine [J]. J Clin Med, 2022, 11: 2303.

100

Stojkic I, Prince BT, Kuehn HS, et al. A novel IKZF1 variant in a family with autosomal dominant CVID: A case for expanding exon coverage in inborn errors of immunity [J]. Clin Immunol, 2024, 264: 110244.

101

Yamashita M, Morio T. AIOLOS variants causing immunodeficiency in human and mice [J]. Front Immunol, 2022, 13: 866582.

102

Hoshino A, Okada S, Yoshida K, et al. Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations [J]. J Allergy Clin Immunol, 2017, 140: 223-231.

103

Sriaroon P, Chang Y, Ujhazi B, et al. Familial immune thrombocytopenia associated with a novel variant in IKZF1 [J]. Front Pediatr, 2019, 7: 139.

104

Yamashita M, Morio T. AIOLOS-associated inborn errors of immunity [J]. J Clin Immunol, 2024, 44: 128.

105

Dieudonné Y, Guffroy A, Vollmer O, et al. IKZF1 loss-of-function variant causes autoimmunity and severe familial antiphospholipid syndrome [J]. J Clin Immunol, 2019, 39: 353-357.

106

Van Nieuwenhove E, Garcia-Perez JE, Helsen C, et al. A kindred with mutant IKAROS and autoimmunity [J]. J Allergy Clin Immunol, 2018, 142: 699-702. e12.

107

Shahin T, Mayr D, Shoeb MR, et al. Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation [J]. Blood Adv, 2022, 6: 2444-2451.

108

Guirguis J, Iosim S, Jones D, et al. Neutrophilic dermatosis in a patient with an IKZF1 variant and a review of monogenic autoinflammatory disorders presenting with neutrophilic dermatoses [J]. Pediatr Dermatol, 2024, 41: 707-713.

109

Shahin T, Kuehn HS, Shoeb MR, et al. Germline biallelic mutation affecting the transcription factor Helios causes pleiotropic defects of immunity [J]. Sci Immunol, 2021, 6: eabe3981.

110

Song C, Pan X, Ge Z, et al. Epigenetic regulation of gene expression by Ikaros, HDAC1 and casein kinase Ⅱ in leukemia [J]. Leukemia, 2016, 30: 1436-1440.

111

Wang H, Song C, Ding Y, et al. Transcriptional regulation of JARID1B/KDM5B histone demethylase by Ikaros, histone deacetylase 1 (HDAC1), and casein kinase 2 (CK2) in B-cell acute lymphoblastic leukemia [J]. J Biol Chem, 2016, 291: 4004-4018.

112

Wada T, Asahi T, Sawamura N. Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells [J]. Biochem Biophys Res Commun, 2016, 477: 388-394.

113

Shen Z, Asa SL, Ezzat S. Ikaros and its interacting partner CtBP target the metalloprotease ADAMTS10 to modulate pituitary cell function [J]. Mol Cell Endocrinol, 2017, 439: 126-132.

114

Tian H, Ge C, Zhao F, et al. Downregulation of AZGP1 by Ikaros and histone deacetylase promotes tumor progression through the PTEN/Akt and CD44s pathways in hepatocellular carcinoma [J]. Carcinogenesis, 2017, 38: 207-217.

115

Hu Y, Salgado Figueroa D, Zhang Z, et al. Lineage-specific 3D genome organization is assembled at multiple scales by IKAROS [J]. Cell, 2023, 186: 5269-5289. e22.

116

Harman CCD, Bailis W, Zhao J, et al. An in vivo screen of noncoding loci reveals that Daedalus is a gatekeeper of an Ikaros-dependent checkpoint during haematopoiesis [J]. Proc Natl Acad Sci U S A, 2021, 118: e1918062118.

117

Alomairi J, Molitor AM, Sadouni N, et al. Integration of high-throughput reporter assays identify a critical enhancer of the Ikzf1 gene [J]. PLoS One, 2020, 15: e0233191.

118

Klangkalya N, Esteve-Sole A, Gil Silva AA, et al. IKAROS protein stability is regulated by its early N-terminal region and C-terminal dimerization domain [J]. Clin Immunol, 2025, 274: 110469.

119

Apostolov A, Litim-Mecheri I, Oravecz A, et al. Sumoylation inhibits the growth suppressive properties of Ikaros [J]. PLoS One, 2016, 11: e0157767.

120

Liu M, Jin J, Ji Y, et al. Hsp90/C terminal Hsc70-interacting protein regulates the stability of Ikaros in acute myeloid leukemia cells [J]. Sci China Life Sci, 2021, 64: 1481-1490.

121

Klink M, Rahman MA, Song C, et al. Mechanistic basis for in vivo therapeutic efficacy of CK2 inhibitor CX-4945 in acute myeloid leukemia [J]. Cancers (Basel), 2021, 13: 1127.

122

Ge Z, Song C, Ding Y, et al. Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia [J]. Leukemia, 2021, 35: 1267-1278.

123

Gowda CS, Song C, Ding Y, et al. Protein signaling and regulation of gene transcription in leukemia: Role of the casein kinase Ⅱ-Ikaros axis [J]. J Investig Med, 2016, 64: 735-739.

124

Cho SJ, Kang H, Kim MY, et al. Site-specific phosphorylation of Ikaros induced by low-dose ionizing radiation regulates cell cycle progression of B lymphoblast through CK2 and AKT activation [J]. Int J Radiat Oncol Biol Phys, 2016, 94: 1207-1218.

125

Payne JL, Song C, Ding Y, et al. Regulation of small GTPase Rab20 by Ikaros in B-cell acute lymphoblastic leukemia [J]. Int J Mol Sci, 2020, 21: 1718.

126

Wang Y, Zheng X, Wang Q, et al. GSK3beta-Ikaros-ANXA4 signaling inhibits high-glucose-induced fibroblast migration [J]. Biochem Biophys Res Commun, 2020, 531: 543-551.

127

Ribeiro ML, Normant E, Roué G. Ikaros as a downstream mediator of BCR blockade therapy in B-cell non-Hodgkin lymphoma [J]. Oncoscience, 2022, 9: 64-65.

128

Dimond A, Gim DH, Ing-Simmons E, et al. PBK/TOPK mediates Ikaros, Aiolos and CTCF displacement from mitotic chromosomes and alters chromatin accessibility at selected C2H2-zinc finger protein binding sites [J]. Nat Commun, 2025, 16: 8348.

129

Gao W, Huang J, Deng K, et al. Endothelial cells sense temozolomide resistance to facilitate monocyte-derived macrophage infiltration in glioblastoma [J]. Drug Resist Updat, 2026, 84: 101329.

130

Liu C, Zheng J, Hao J, et al. Lactylation-related genes serve as potential markers for the diagnosis and immune infiltration in rheumatoid arthritis [J]. Autoimmunity, 2025, 58: 2474217.

2026年第61卷第9期

PDF下载

105

引用本文

BibTeX

文章信息

doi: 10.16438/j.0513-4870.2026-0512

接收时间：2026-05-03
首发时间：2026-10-22
出版时间：2026-09-12

补充材料

相关文章

文章信息

作者

出版历史

收稿日期：2026-05-03
修回日期：2026-05-28

基金

作者信息

中国医学科学院北京协和医学院, 药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050

通讯作者:

卢多，Tel: 86-10-63039979，E-mail: luduo@imm.ac.cn

参考文献

分享链接

https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2026-0512

分享至

全文二维码

扫描看全文

引用本文

BibTeX

本文的引用情况

2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

关闭全屏

BibTeX
EndNote
RefWorks
TxT

Drug name	Degradation target	Related diseases in the study
CC-122 (avadomide)^[7]	Ikaros, Aiolos, ZFP91, ZMYM2	MM, DLBCL, FL, GBM, HCC
CC-99282^[7]	Ikaros, Aiolos	DLBCL, NHL, BCL
CC-220 (iberdomide)^{[7, 17]}	Ikaros, Aiolos	MM, BCL
CC-885^[7]	GSPT1, Aiolos, CDK4, BNIP3L	MM, AML
CC-90009 (eragidomide)^[7]	GSPT1	AML, MDS
CFT7455^[7]	Ikaros, Aiolos	MM, NHL, DLBCL
BTX-1188^[7]	GSPT1, Ikaros, Aiolos, CK1α	AML, NHL, solid tumor
CC-91633^[7]	CK1α	AML, MDS
CC-92480 (mezigdomide)^[7]	Ikaros, Aiolos	MM, TCL
CC-647^[7]	PLZF	APL
CC-3060^[7]	PLZF	APL
DIX-01^[9]	Ikaros, Aiolos, GSPT1	AML
FPT-2216^[10]	Ikaros, Aiolos, CK1α	Lymphoma
MGD-22^[12]	Ikaros, Helios, Aiolos	MM, DLBCL, AML
MGD-28^[11]	Ikaros, Helios, Aiolos, CK1α	MM
NX-2127^[13]	Ikaros, Aiolos, BTK	CLL
KT-413^[14]	Ikaros, Aiolos, IRAK4	DLBCL
Compound 55^[18]	Helios	Cancer
Lead degrader 31^[19]	Helios, CK1α	Cancer
PVTX-405^[20]	Helios	CRC
NVP-DKY709^[21]	Helios	Solid tumor
BC6^[25]	Bcl-6, Ikaros, Aiolos	DLBCL
ALV-07-082-03^[26]	CDK4/6, Helios	T-ALL

Drug name

Degradation target

Related diseases in the study

CC-122 (avadomide)^[7]

Ikaros, Aiolos, ZFP91, ZMYM2

MM, DLBCL, FL, GBM, HCC

CC-99282^[7]

Ikaros, Aiolos

DLBCL, NHL, BCL

CC-220 (iberdomide)^{[7, 17]}

Ikaros, Aiolos

MM, BCL

CC-885^[7]

GSPT1, Aiolos, CDK4, BNIP3L

MM, AML

CC-90009 (eragidomide)^[7]

GSPT1

AML, MDS

CFT7455^[7]

Ikaros, Aiolos

MM, NHL, DLBCL

BTX-1188^[7]

GSPT1, Ikaros, Aiolos, CK1α

AML, NHL, solid tumor

CC-91633^[7]

CK1α

AML, MDS

CC-92480 (mezigdomide)^[7]

Ikaros, Aiolos

MM, TCL

CC-647^[7]

PLZF

APL

CC-3060^[7]

PLZF

APL

DIX-01^[9]

Ikaros, Aiolos, GSPT1

AML

FPT-2216^[10]

Ikaros, Aiolos, CK1α

Lymphoma

MGD-22^[12]

Ikaros, Helios, Aiolos

MM, DLBCL, AML

MGD-28^[11]

Ikaros, Helios, Aiolos, CK1α

NX-2127^[13]

Ikaros, Aiolos, BTK

CLL

KT-413^[14]

Ikaros, Aiolos, IRAK4

DLBCL

Compound 55^[18]

Helios

Cancer

Lead degrader 31^[19]

Helios, CK1α

Cancer

PVTX-405^[20]

Helios

CRC

NVP-DKY709^[21]

Helios

Solid tumor

BC6^[25]

Bcl-6, Ikaros, Aiolos

DLBCL

ALV-07-082-03^[26]

CDK4/6, Helios

T-ALL

Mutation region	Protein	Mutation site	Disease
N	Ikaros	M31V^[91], V52L^[91], V53M^[91], D81N^[91], S105L^[91]	B-ALL
	Helios	R106W^[107]	AOSD
	Aiolos	E82K^[104]	SLE, HT, AIH, asthma
NZF	Ikaros	D120V^[90]	SLE
		N159S^{[91, 93, 102]}	T-ALL, BCP-ALL, CID
		N159T^[93]	CID
		N160S^[101]	CLL
		R162Q^{[99, 102]}	IgAV, CVID, ITP
		R162W^[102]	BCP-ALL
		H167R^[105]	APS
		R183H^[92]	NXG
		L188V^[106]	APS, SLE
		Y210C^[102]	Pancytopenia
		L132P^[97], R143W^[98], H167Y^[100]	CVID
		C147R^[102], H195R^[103], R213^*[96]	ITP
		N159Y^[90], R162P^[91], H163Y^[91], D186fs^[91]	B-ALL
	Helios	Y220^*[94]	CID
	Aiolos	G159R^[101]	EBVAL, DG
		N160S^[101]	MM, DG
		L162R^[104]	CLL
		G191R^[95]	CID
IntZF	Ikaros	S427^*[96]	DG
		S455Rfs^*4^[108]	ND
		D252N^[91], R258P^[91], M306^[91], T333A^[91], G337S^[91], M347V^[91], Y348C^[91], A365V^[91], C394^[91], R423C^[91], A434G^[91], L449F^[91], M459V^[91]	B-ALL
	Helios	N220S^[107]	ES
		R291^*[107]	DG, ITP
		I325V^[109], V347M^[107]	DG
		Y359C^[107]	ITP
	Aiolos	Q402^*[104]	ITP
CZF	Ikaros	C467R^[96]	ES
		M476T^[91]	B-ALL
		M494V^[91]	CNSL
		M494fs^*86^[91]	DG
		R502L^[96]	ITP, BL

Mutation region

Protein

Mutation site

Disease

Ikaros

M31V^[91], V52L^[91], V53M^[91], D81N^[91], S105L^[91]

B-ALL

Helios

R106W^[107]

AOSD

Aiolos

E82K^[104]

SLE, HT, AIH, asthma

NZF

Ikaros

D120V^[90]

SLE

N159S^{[91, 93, 102]}

T-ALL, BCP-ALL, CID

N159T^[93]

CID

N160S^[101]

CLL

R162Q^{[99, 102]}

IgAV, CVID, ITP

R162W^[102]

BCP-ALL

H167R^[105]

APS

R183H^[92]

NXG

L188V^[106]

APS, SLE

Y210C^[102]

Pancytopenia

L132P^[97], R143W^[98], H167Y^[100]

CVID

C147R^[102], H195R^[103], R213^*[96]

ITP

N159Y^[90], R162P^[91], H163Y^[91], D186fs^[91]

B-ALL

Helios

Y220^*[94]

CID

Aiolos

G159R^[101]

EBVAL, DG

N160S^[101]

MM, DG

L162R^[104]

CLL

G191R^[95]

CID

IntZF

Ikaros

S427^*[96]

S455Rfs^*4^[108]

D252N^[91], R258P^[91], M306^*[91], T333A^[91], G337S^[91], M347V^[91], Y348C^[91], A365V^[91], C394^*[91], R423C^[91], A434G^[91], L449F^[91], M459V^[91]

B-ALL

Helios

N220S^[107]

R291^*[107]

DG, ITP

I325V^[109], V347M^[107]

Y359C^[107]

ITP

Aiolos

Q402^*[104]

ITP

CZF

Ikaros

C467R^[96]

M476T^[91]

B-ALL

M494V^[91]

CNSL

M494fs^*86^[91]

R502L^[96]

ITP, BL