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Article(id=1322190721742918030, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322190415911043621, articleNumber=null, orderNo=null, doi=10.16016/j.2097-0927.202507019, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1751644800000, receivedDateStr=2025-07-05, revisedDate=1754409600000, revisedDateStr=2025-08-06, acceptedDate=null, acceptedDateStr=null, onlineDate=1793164433178, onlineDateStr=2026-10-28, pubDate=1759161600000, pubDateStr=2025-09-30, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1793164433178, onlineIssueDateStr=2026-10-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1793164433178, creator=13701087609, updateTime=1793164433178, updator=13701087609, issue=Issue{id=1322190415911043621, tenantId=1146029695717560320, journalId=1319373162502258839, year='2025', volume='47', issue='18', pageStart='2145', pageEnd='2288', issueExtLink='null', onlineDate='null', pubDate='1759161600000', pubDateStr='2025-09-30', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1793164360263, creator='13701087609', updateTime=1793164574764, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1322191316100960652, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322190415911043621, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1322191316105154957, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322190415911043621, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2237, endPage=2244, ext={EN=ArticleExt(id=1322190722166542735, articleId=1322190721742918030, tenantId=1146029695717560320, journalId=1319373162502258839, language=EN, title=Impact of molecular heterogeneity of NPM1 mutations on prognosis of acute myeloid leukemia: a clinical report of 86 cases, columnId=1320435174995772212, journalTitle=Journal of Army Medical University, columnName=Clinical Medicine, runingTitle=null, highlight=null, articleAbstract=
Objective

To investigate the impact of nucleophosmin 1-mutated (NPM1m) subtypes, variant allele frequency (VAF) and co-mutations on the survival outcomes of patients with acute myeloid leukemia (AML).

Methods

Clinical data, mutation status, and outcomes of 86 NPM1m-AML patients admitted in Department of Hematology, First Hospital of Lanzhou University between June 2017 and September 2024 were collected and retrospectively analyzed. Spearman correlation analysis, Kaplan-Meier curve analysis, Log-rank test, and Cox regression analysis was applied for correlation analysis, survival analysis, and factors affecting survival.

Results

The overall survival (OS) was significantly shorter in the Rares subtype of NPM1m than the ABD subtype (median OS: 164 d vs 416 d, P=0.043). The VAF of NPM1mwas positively correlated with the initial peripheral blood white blood cell count and lactate dehydrogenase (LDH) level (P<0.05). OS was reduced when VAF was ≥0.37 (median OS: 164 d vs 730 d, P=0.003). The presence of myelodysplasia-related gene (MR) mutations was associated with a poorer prognosis when compared to the MR wild-type (median OS: 45 d vs 395 d, P<0.001). The triple mutation of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and DNMT3A also indicated a worse prognosis than the non-triple mutation (median OS: 173 d vs 483 d, P=0.007). The presence of PTPN11 mutations was associated with improved OS (median OS: 395 d vs 240 d, P=0.027), while the patients with coexistence of N/KRAS mutations trended toward better prognosis than the wild-type patients (median OS: 662 d vs 189 d) though no statistical significance (P=0.070). Multivariate analysis revealed that LDH (HR=1.002, 95%CI: 1.000~1.003, P=0.005), NPM1m VAF (HR=2.415, 95%CI: 1.208~4.829, P=0.013), Rares subtype (HR=3.037, 95%CI: 1.134~8.136, P=0.027), and MR mutations (HR=5.283, 95%CI: 1.991~14.017, P<0.001) were independent risk factors associated with OS in the patients.

Conclusion

Molecular heterogeneity of NPM1m should be taken into account in prognostic stratification of NPM1m-AML. Factors including the Rares subtype, VAF≥0.37, coexistence of FLT3-ITD and DNMT3A mutations, and MR mutations are associated with poor prognosis of NPM1m-AML. The presence of PTPN11 mutations improves the prognosis, while the presence of N/KRAS mutations shows a trend toward better prognosis. LDH, NPM1m VAF, Rares subtype, and MR mutations are independent risk factors affecting OS of patients with NPM1m-AML.

, authors=Xiaoda YU1, Jiangang GUO1, An’an WANG1, Jiajing LI1, Bei LIU2, authorsList=Xiaoda YU, Jiangang GUO, An’an WANG, Jiajing LI, Bei LIU, authorCompany=null, correspAuthors=Bei LIU, authorNote=null, correspAuthorsNote=null, copyrightStatement=© 2025 Journal of Army Medical University, copyrightOwner=Editorial Office of Journal of Army Medical University, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1322190724934783386, articleId=1322190721742918030, tenantId=1146029695717560320, journalId=1319373162502258839, language=CN, title=核仁磷酸蛋白1突变的分子异质性对急性髓系白血病预后的影响, columnId=1320435175822050102, journalTitle=陆军军医大学学报, columnName=论著·临床医学, runingTitle=null, highlight=null, articleAbstract=
目的

探讨核仁磷酸蛋白1突变（nucleophosmin 1-mutated，NPM1m）的分型、变异等位基因频率（variant allele frequency，VAF）、共突变等对急性髓系白血病（acute myeloid leukemia，AML）患者预后的影响。

方法

回顾性分析2017年6月至2024年9月就诊于兰州大学第一医院血液科86例NPM1m-AML患者的临床资料及基因突变信息与生存情况，相关性分析采用Spearman相关系数，生存分析采用Kaplan-Meier曲线和Log-rank检验，使用Cox回归分析探究生存影响因素。

结果

NPM1m分型为罕见分型（Rares型）的患者总生存期（overall survival，OS）较ABD型缩短（中位OS：164天vs 416天，P=0.043）。NPM1m VAF值与初诊外周血白细胞计数、乳酸脱氢酶（lactate dehydrogenase，LDH）含量呈正相关（P<0.05），VAF≥0.37时OS缩短（中位OS：164天vs 730天，P=0.003）。合并骨髓增生异常相关基因（myelodysplasia-related gene，MR）突变较MR野生型预后差（中位OS：45天vs 395天，P<0.001）、FMS样酪氨酸激酶3内部串联重复（FMS-like tyrosine kinase 3-internal tandem duplication，FLT3-ITD）及DNMT3A三突变较非三突变预后差（中位OS：173 d vs 483 d，P=0.007）。合并PTPN11突变改善预后（中位OS：395 d vs 240 d，P=0.027），而合并N/KRAS突变较野生型患者呈现出预后更好的趋势（中位OS：662 d vs 189 d，P=0.070），但差异无统计学意义。多因素Cox分析显示LDH（HR=1.002，95%CI：1.000~1.003，P=0.005）、NPM1m VAF值（HR=2.415，95%CI：1.208~4.829，P=0.013）、Rares型（HR=3.037，95%CI：1.134~8.136，P=0.027）、MR突变（HR=5.283，95%CI：1.991~14.017，P<0.001）为患者OS相关的独立危险因素。

结论

NPM1m-AML的预后分层需结合NPM1m的分子异质性，Rares型、VAF≥0.37、合并FLT3-ITD及DNMT3A突变、MR突变是不良预后因素，合并PTPN11突变改善患者预后，合并N/KRAS显示出预后更好的趋势。LDH、NPM1m VAF值、Rares型、MR突变是影响NPM1m-AML患者OS的独立危险因素。

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刘蓓，Email：
LIU Bei，E-mail：
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Blood，2018，131（25）：2816-2825., articleTitle=High NPM1-mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML, refAbstract=null), Reference(id=1322190731259793881, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, doi=10.1182/blood.2024024310, pmid=null, pmcid=null, year=2024, volume=144, issue=7, pageStart=714, pageEnd=728, url=null, language=null, rfNumber=8, rfOrder=7, authorNames=OTHMAN J, POTTER N, IVEY A, journalName=Blood, refType=null, unstructuredReference=OTHMAN J，POTTER N，IVEY A，et al. Molecular，clinical，and therapeutic determinants of outcome in NPM1-mutated AML［J］. Blood，2024，144（7）：714-728., articleTitle=Molecular，clinical，and therapeutic determinants of outcome in NPM1-mutated AML, refAbstract=null), Reference(id=1322190731347874266, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, doi=10.1002/ajh.26730, pmid=null, pmcid=null, year=2022, volume=97, issue=12, pageStart=E462, pageEnd=E465, url=null, language=null, rfNumber=9, rfOrder=8, authorNames=WRIGHT M F, POZDNYAKOVA O, HASSERJIAN R P, journalName=Am J Hematol, refType=null, unstructuredReference=WRIGHT M F，POZDNYAKOVA O，HASSERJIAN R P，et al. Secondary-type mutations do not impact prognosis in acute myelogenous leukemia AML with mutated NPM1［J］. Am J Hematol，2022，97（12）：E462-E465., articleTitle=Secondary-type mutations do not impact prognosis in acute myelogenous leukemia AML with mutated NPM1, refAbstract=null), Reference(id=1322190731414983131, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, doi=10.1371/journal.pone.0109759, pmid=null, pmcid=null, year=2014, volume=9, issue=10, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=10, rfOrder=9, authorNames=PASTORE F, GREIF P A, SCHNEIDER S, journalName=PLoS One, refType=null, unstructuredReference=PASTORE F，GREIF P A，SCHNEIDER S，et al. The NPM1 mutation type has no impact on survival in cytogenetically normal AML［J］. PLoS One，2014，9（10）：e109759., articleTitle=The NPM1 mutation type has no impact on survival in cytogenetically normal AML, refAbstract=null), Reference(id=1322190731482091996, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, doi=10.1080/10428194.2023.2294695, pmid=null, pmcid=null, year=2024, volume=65, issue=4, pageStart=511, pageEnd=515, url=null, language=null, rfNumber=11, rfOrder=10, authorNames=MUTTI M, CORDELLA S, PARISOTTO A, journalName=Leuk Lymphoma, refType=null, unstructuredReference=MUTTI M，CORDELLA S，PARISOTTO A，et al. Characteristics and clinical behavior of acute myeloid leukemia harboring rare non-A/B/D nucleophosmin （NPM1） gene mutation subtypes：a single-center experience and review of the literature［J］. Leuk Lymphoma，2024，65（4）：511-515., articleTitle=Characteristics and clinical behavior of acute myeloid leukemia harboring rare non-A/B/D nucleophosmin （NPM1） gene mutation subtypes：a single-center experience and review of the literature, refAbstract=null), Reference(id=1322190731549200861, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, doi=10.1038/s41375-022-01534-z, pmid=null, pmcid=null, year=2022, volume=36, issue=5, pageStart=1390, pageEnd=1400, url=null, language=null, rfNumber=12, rfOrder=11, authorNames=FOURNIER E, HEIBLIG M, LESPINASSE C, journalName=Leukemia, refType=null, unstructuredReference=FOURNIER E，HEIBLIG M，LESPINASSE C，et al. Molecular heterogeneity and measurable residual disease of rare NPM1 mutations in acute myeloid leukemia：a nationwide experience from the GBMHM study group［J］. Leukemia，2022，36（5）：1390-1400., articleTitle=Molecular heterogeneity and measurable residual disease of rare NPM1 mutations in acute myeloid leukemia：a nationwide experience from the GBMHM study group, refAbstract=null), Reference(id=1322190731675029982, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, doi=10.1002/ajh.25454, pmid=null, pmcid=null, year=2019, volume=94, issue=6, pageStart=E158, pageEnd=E160, url=null, language=null, rfNumber=13, rfOrder=12, authorNames=ABBAS H A, RAVANDI F, LOGHAVI S, journalName=Am J Hematol, refType=null, unstructuredReference=ABBAS H A，RAVANDI F，LOGHAVI S，et al. NPM1 mutant variant allele frequency correlates with leukemia burden but does not provide prognostic information in NPM1-mutated acute myeloid leukemia［J］. Am J Hematol，2019，94（6）：E158-E160., articleTitle=NPM1 mutant variant allele frequency correlates with leukemia burden but does not provide prognostic information in NPM1-mutated acute myeloid leukemia, refAbstract=null), Reference(id=1322190731733750239, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, doi=10.13885/j.issn.1000-2812.2023.04.006, pmid=null, pmcid=null, year=2023, volume=49, issue=4, pageStart=32, pageEnd=38, url=null, language=null, rfNumber=14, rfOrder=13, authorNames=杨晓晓, 罗兴春, 郭元成, journalName=兰州大学学报（医学版）, refType=null, unstructuredReference=杨晓晓，罗兴春，郭元成，等. NPM1、FLT3、DNMT3A共突变急性髓系白血病的临床特征、预后及生物信息学分析［J］. 兰州大学学报（医学版），2023，49（4）：32-38., articleTitle=NPM1、FLT3、DNMT3A共突变急性髓系白血病的临床特征、预后及生物信息学分析, refAbstract=null), Reference(id=1322190731792470496, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, doi=10.13885/j.issn.1000-2812.2023.04.006, pmid=null, pmcid=null, year=2023, volume=49, issue=4, pageStart=32, pageEnd=38, url=null, language=null, rfNumber=14, rfOrder=14, authorNames=YANG X X, LUO X C, GUO Y C, journalName=J Lanzhou Univ Med Sci, refType=null, unstructuredReference=YANG X X，LUO X C，GUO Y C，et al. Clinical characteristics，prognosis and bioinformatics analysis of NPM1，FLT3 and DNMT3A co-mutant acute myeloid leukemia［J］. J Lanzhou Univ Med Sci，2023，49（4）：32-38., articleTitle=Clinical characteristics，prognosis and bioinformatics analysis of NPM1，FLT3 and DNMT3A co-mutant acute myeloid leukemia, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1322190725219996060, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, xref=1, ext=[AuthorCompanyExt(id=1322190725232578973, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, companyId=1322190725219996060, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1the First Clinical Medical College of Lanzhou University, the First Hospital of Lanzhou University，Lanzhou，Gansu，China), AuthorCompanyExt(id=1322190725245161886, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, companyId=1322190725219996060, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1兰州大学：第一临床医学院，甘肃 兰州)]), AuthorCompany(id=1322190725312270751, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, xref=2, ext=[AuthorCompanyExt(id=1322190725396156832, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, companyId=1322190725312270751, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2Department of Hematology, the First Hospital of Lanzhou University，Lanzhou，Gansu，China), AuthorCompanyExt(id=1322190725421322657, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, companyId=1322190725312270751, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2兰州大学：第一医院血液科，甘肃 兰州)])], figs=[ArticleFig(id=1322190729334608324, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=EN, label=Figure 1, caption=Impact of NPM1m subtypes on OS in AML patients, figureFileSmall=l4Gj1gQU2H7QMdg8DUVEDQ==, figureFileBig=lf8rKtccZGGRCLO9/omsqQ==, tableContent=null), ArticleFig(id=1322190729410105797, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=CN, label=图1, caption=NPM1m分型对OS的影响

A：Impact of NPM1m subtypes on OS in all AML patients； B：Impact of NPM1m subtypes on OS in AML patients aged 60 years and older

, figureFileSmall=l4Gj1gQU2H7QMdg8DUVEDQ==, figureFileBig=lf8rKtccZGGRCLO9/omsqQ==, tableContent=null), ArticleFig(id=1322190729691124166, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=EN, label=Figure 2, caption=NPM1m VAF characteristics and their impact on OS in the AML patients, figureFileSmall=lDLTvsrP6lzwyTcde2Jw3A==, figureFileBig=2RKMirsXMEettE7UkWrgyw==, tableContent=null), ArticleFig(id=1322190729762427335, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=CN, label=图2, caption=NPM1m VAF特征及对OS的影响

A：Correlation between NPM1m VAF and WBC count，LDH level，and proportion of bone marrow blasts； B：Impact of NPM1m VAF on OS in all AML Patients； C：Impact of NPM1m VAF on OS in patients aged 60 years and older； D：Impact of NPM1m VAF on OS in patients with FLT3-ITD mutation. FLT3-ITDm：FLT3-ITD mutation

, figureFileSmall=lDLTvsrP6lzwyTcde2Jw3A==, figureFileBig=2RKMirsXMEettE7UkWrgyw==, tableContent=null), ArticleFig(id=1322190729833730504, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=EN, label=Figure 3, caption=NPM1m co-mutation profile and Heatmap of gene exclusivity correlations, figureFileSmall=+vyn5g2XmQcXUeFrGP7KWg==, figureFileBig=BZWgej0iya7oVQI9GQbNGw==, tableContent=null), ArticleFig(id=1322190730005696969, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=CN, label=图3, caption=NPM1m共突变图谱及基因互斥相关性热图

A：Co-mutation profile； B：Gene correlation heatmap. a：P<0.05，b：P<0.01，c：P<0.001

, figureFileSmall=+vyn5g2XmQcXUeFrGP7KWg==, figureFileBig=BZWgej0iya7oVQI9GQbNGw==, tableContent=null), ArticleFig(id=1322190730072805834, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=EN, label=Figure 4, caption=NPM1m co-mutations impact on OS in the AML patients, figureFileSmall=cA5Fxmx0u/qNm8KEYlXlmQ==, figureFileBig=BAuOUcRRSmpWI5gxFrEskw==, tableContent=null), ArticleFig(id=1322190730144109003, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=CN, label=图4, caption=NPM1m共突变对OS的影响

A：Impact of FLT3-ITD mutation on OS in all patients. FLT3-ITDw：FLT3-ITD wild-type； B：Impact of co-mutations in NPM1，FLT3-ITD，and DNMT3A on OS in all patients. DNMT3Am：DNMT3A mutation，DNMT3Aw：DNMT3A wild-type； C：Impact of MR mutation on OS in all patients. MRm：MR mutation，MRw：MR wild-type； D：Impact of N/KRAS mutation on OS in all patients. N/KRASm：N/KRAS mutation，N/KRASw：N/KRAS wild-type； E：Impact of PTPN11 mutation on OS in all patients PTPN11m：PTPN11 mutation，PTPN11w：PTPN11 wild-type

, figureFileSmall=cA5Fxmx0u/qNm8KEYlXlmQ==, figureFileBig=BAuOUcRRSmpWI5gxFrEskw==, tableContent=null), ArticleFig(id=1322190730215412172, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=EN, label=Table 1, caption=

Clinical characteristics and molecular heterogeneity of 86 patients with NPM1m-AML ［n（%），M（P25，P75），x¯±s］

, figureFileSmall=null, figureFileBig=null, tableContent=
CharacteristicNPM1m subtypesPχ2/t/ZNPM1m VAFPχ2/t/Z
ABD（n=69）Rares（n=13）VAF<0.37
（n=34）		VAF≥0.37
（n=33）
Sex0.7620.0910.3890.742
Male35（50.72）6（46.15）18（52.94）14（42.42）
Female34（49.28）7（53.85）16（47.06）19（57.58）
Age/years56.03±13.8856.54±16.310.9060.11857.29±14.5957.39±12.210.9760.030
FAB classification0.5283.1810.03610.254
M15（7.25）1（7.69）2（5.88）2（6.06）
M222（31.88）2（15.38）9（26.48）11（33.34）
M49（13.04）3（23.08）1（2.94）9（27.27）
M529（42.03）5（38.46）18（52.94）9（27.27）
Undetermined4（5.80）2（15.38）4（11.76）2（6.06）
2022 ELN0.6041.0090.0924.761
Favorable35（50.72）8（61.54）20（58.82）13（39.39）
Intermediate31（44.93）4（30.77）14（41.18）17（51.52）
Poor3（4.35）1（7.69）0（0.00）3（9.09）
Karyotype0.9050.0140.6590.195
Normal63（91.30）12（92.31）31（91.18）29（87.88）
Abnormal6（8.70）1（7.69）3（8.82）4（12.12）
WBC count/（×10⁹/L）34.66
（8.12，76.03）		4.75
（2.20，43.00）		0.035-2.11423.20
（13.68，42.04）		42.13
（11.76，76.03）		0.0481.982
Hemoglobin/（g/L）80.49±21.2476.61±29.600.574-0.56583.24±22.5172.30±20.690.043-2.068
Platelet count/（×10⁹/L）53.00
（26.00，96.00）		35.00
（17.00，70.00）		0.218-1.23254.00
（27.00，117.75）		47.00
（19.00，75.00）		0.249-1.154
LDH/（U/L）493.00
（310.00，720.00）		384.00
（286.00，694.00）		0.839-0.203337.00
（329.00，627.75）		571.00
（384.00，767.00）		0.0112.558
Bone marrow blasts/%64.50
（46.00，80.00）		55.00
（40.50，86.50）		0.995-0.00665.75
（41.38，79.50）		75.50
（46.00，80.50）		0.4440.765
FLT3-ITD34（49.28）5（38.46）0.4740.51314（41.18）20（60.61）0.1122.529
DNMT3A29（42.03）1（7.69）0.0185.55911（32.35）18（54.55）0.0673.360
IDH217（24.64）2（15.38）0.4680.5264（11.76）8（24.24）0.1831.773
WT110（14.49）3（23.08）0.4370.6044（11.76）4（12.12）0.9640.002
NRAS13（18.84）2（15.38）0.7670.0878（23.53）6（18.18）0.5900.290
IDH111（15.94）1（7.69）0.4400.5966（17.65）6（18.18）0.9540.003
FLT3-TKD9（13.04）2（15.38）0.8200.0527（20.59）4（12.12）0.3500.875
PTPN117（10.14）1（7.69）0.7850.0755（14.71）3（9.09）0.4790.502
TET26（8.70）0（0.00）0.2691.2201（2.94）3（9.09）0.2881.128
CEBPA4（5.80）1（7.69）0.7930.0691（2.94）0（0.00）0.3210.985
), ArticleFig(id=1322190730307686861, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=CN, label=表1, caption=

86例NPM1m-AML患者临床特征与分子异质性 ［例（%），M（P25，P75），x¯±s］

, figureFileSmall=null, figureFileBig=null, tableContent=
CharacteristicNPM1m subtypesPχ2/t/ZNPM1m VAFPχ2/t/Z
ABD（n=69）Rares（n=13）VAF<0.37
（n=34）		VAF≥0.37
（n=33）
Sex0.7620.0910.3890.742
Male35（50.72）6（46.15）18（52.94）14（42.42）
Female34（49.28）7（53.85）16（47.06）19（57.58）
Age/years56.03±13.8856.54±16.310.9060.11857.29±14.5957.39±12.210.9760.030
FAB classification0.5283.1810.03610.254
M15（7.25）1（7.69）2（5.88）2（6.06）
M222（31.88）2（15.38）9（26.48）11（33.34）
M49（13.04）3（23.08）1（2.94）9（27.27）
M529（42.03）5（38.46）18（52.94）9（27.27）
Undetermined4（5.80）2（15.38）4（11.76）2（6.06）
2022 ELN0.6041.0090.0924.761
Favorable35（50.72）8（61.54）20（58.82）13（39.39）
Intermediate31（44.93）4（30.77）14（41.18）17（51.52）
Poor3（4.35）1（7.69）0（0.00）3（9.09）
Karyotype0.9050.0140.6590.195
Normal63（91.30）12（92.31）31（91.18）29（87.88）
Abnormal6（8.70）1（7.69）3（8.82）4（12.12）
WBC count/（×10⁹/L）34.66
（8.12，76.03）		4.75
（2.20，43.00）		0.035-2.11423.20
（13.68，42.04）		42.13
（11.76，76.03）		0.0481.982
Hemoglobin/（g/L）80.49±21.2476.61±29.600.574-0.56583.24±22.5172.30±20.690.043-2.068
Platelet count/（×10⁹/L）53.00
（26.00，96.00）		35.00
（17.00，70.00）		0.218-1.23254.00
（27.00，117.75）		47.00
（19.00，75.00）		0.249-1.154
LDH/（U/L）493.00
（310.00，720.00）		384.00
（286.00，694.00）		0.839-0.203337.00
（329.00，627.75）		571.00
（384.00，767.00）		0.0112.558
Bone marrow blasts/%64.50
（46.00，80.00）		55.00
（40.50，86.50）		0.995-0.00665.75
（41.38，79.50）		75.50
（46.00，80.50）		0.4440.765
FLT3-ITD34（49.28）5（38.46）0.4740.51314（41.18）20（60.61）0.1122.529
DNMT3A29（42.03）1（7.69）0.0185.55911（32.35）18（54.55）0.0673.360
IDH217（24.64）2（15.38）0.4680.5264（11.76）8（24.24）0.1831.773
WT110（14.49）3（23.08）0.4370.6044（11.76）4（12.12）0.9640.002
NRAS13（18.84）2（15.38）0.7670.0878（23.53）6（18.18）0.5900.290
IDH111（15.94）1（7.69）0.4400.5966（17.65）6（18.18）0.9540.003
FLT3-TKD9（13.04）2（15.38）0.8200.0527（20.59）4（12.12）0.3500.875
PTPN117（10.14）1（7.69）0.7850.0755（14.71）3（9.09）0.4790.502
TET26（8.70）0（0.00）0.2691.2201（2.94）3（9.09）0.2881.128
CEBPA4（5.80）1（7.69）0.7930.0691（2.94）0（0.00）0.3210.985
), ArticleFig(id=1322190730395767246, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=EN, label=Table 2, caption=

Univariate Cox regression analysis of OS in NPM1m-AML patients

, figureFileSmall=null, figureFileBig=null, tableContent=
Influencing factorsBSEWaldHR95%CIP
Sex0.1970.2660.5521.2180.724~2.0500.457
Age/years0.0160.0102.5501.0160.996~1.0360.110
Karyotype0.1980.4330.2081.2180.521~2.8490.648
WBC count0.0080.00214.3551.0081.004~1.012<0.001
Hemoglobin-0.0010.0060.0430.9990.987~1.0110.835
Platelet count-0.0040.0022.7780.9960.991~1.0010.096
LDH0.001<0.00110.2651.0011.000~1.0010.001
Bone marrow blasts0.0030.0060.2901.0030.992~1.0150.590
NPM1m VAF
（<0.37 vs ≥0.37）		0.9490.3268.4532.5821.362~4.8940.004
Rares subtype0.6830.3443.9471.9801.009~3.8830.047
FLT3-ITD0.4340.2672.6431.5440.915~2.6060.104
DNMT3A0.4900.2733.2181.6320.956~2.7870.073
IDH2-0.1270.3200.1570.8810.471~1.6500.692
WT10.2910.3380.7391.3370.689~2.5960.390
IDH1-0.5930.4691.6020.5520.220~1.3850.206
FLT3-TKD-0.2470.4040.3730.7810.354~1.7250.542
PTPN11-1.9171.0093.6050.1470.020~1.0640.058
TET20.0750.5970.0161.0770.334~3.4740.901
CEBPA0.5710.4721.4691.7710.703~4.4620.226
N/KRAS-0.6800.3843.1470.5060.239~1.0740.076
MR1.0950.34010.3602.9901.535~5.8250.001
), ArticleFig(id=1322190730500624847, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=CN, label=表2, caption=

NPM1m-AML患者OS的单因素Cox 回归分析

, figureFileSmall=null, figureFileBig=null, tableContent=
Influencing factorsBSEWaldHR95%CIP
Sex0.1970.2660.5521.2180.724~2.0500.457
Age/years0.0160.0102.5501.0160.996~1.0360.110
Karyotype0.1980.4330.2081.2180.521~2.8490.648
WBC count0.0080.00214.3551.0081.004~1.012<0.001
Hemoglobin-0.0010.0060.0430.9990.987~1.0110.835
Platelet count-0.0040.0022.7780.9960.991~1.0010.096
LDH0.001<0.00110.2651.0011.000~1.0010.001
Bone marrow blasts0.0030.0060.2901.0030.992~1.0150.590
NPM1m VAF
（<0.37 vs ≥0.37）		0.9490.3268.4532.5821.362~4.8940.004
Rares subtype0.6830.3443.9471.9801.009~3.8830.047
FLT3-ITD0.4340.2672.6431.5440.915~2.6060.104
DNMT3A0.4900.2733.2181.6320.956~2.7870.073
IDH2-0.1270.3200.1570.8810.471~1.6500.692
WT10.2910.3380.7391.3370.689~2.5960.390
IDH1-0.5930.4691.6020.5520.220~1.3850.206
FLT3-TKD-0.2470.4040.3730.7810.354~1.7250.542
PTPN11-1.9171.0093.6050.1470.020~1.0640.058
TET20.0750.5970.0161.0770.334~3.4740.901
CEBPA0.5710.4721.4691.7710.703~4.4620.226
N/KRAS-0.6800.3843.1470.5060.239~1.0740.076
MR1.0950.34010.3602.9901.535~5.8250.001
), ArticleFig(id=1322190730571928016, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=EN, label=Table 3, caption=

Multivariate Cox regression analysis of OS in NPM1m-AML patients

, figureFileSmall=null, figureFileBig=null, tableContent=
Influencing factorsBSEWaldHR95%CIP
LDH0.0020.0017.9711.0021.000~1.0030.005
NPM1m VAF
（<0.37 vs ≥0.37）		0.8820.3536.2242.4151.208~4.8290.013
Rares subtype1.1110.5034.8833.0371.134~8.1360.027
MR1.6650.49811.1805.2831.991~14.017<0.001
), ArticleFig(id=1322190730655814097, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190721742918030, language=CN, label=表3, caption=

NPM1m-AML患者OS的多因素Cox 回归分析

, figureFileSmall=null, figureFileBig=null, tableContent=
Influencing factorsBSEWaldHR95%CIP
LDH0.0020.0017.9711.0021.000~1.0030.005
NPM1m VAF
（<0.37 vs ≥0.37）		0.8820.3536.2242.4151.208~4.8290.013
Rares subtype1.1110.5034.8833.0371.134~8.1360.027
MR1.6650.49811.1805.2831.991~14.017<0.001
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核仁磷酸蛋白1突变的分子异质性对急性髓系白血病预后的影响
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于晓达 1 , 郭建刚 1 , 王安安 1 , 李佳璟 1 , 刘蓓 2
陆军军医大学学报 | 论著·临床医学 2025,47(18): 2237-2244
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陆军军医大学学报 |论著·临床医学 2025 , 47 (18) : 2237 -2244
核仁磷酸蛋白1突变的分子异质性对急性髓系白血病预后的影响
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于晓达1, 郭建刚1, 王安安1, 李佳璟1, 刘蓓2
作者信息
  • 1兰州大学：第一临床医学院，甘肃 兰州
  • 2兰州大学：第一医院血液科，甘肃 兰州
通讯作者:
刘蓓，Email：
LIU Bei，E-mail：
Impact of molecular heterogeneity of NPM1 mutations on prognosis of acute myeloid leukemia: a clinical report of 86 cases
Xiaoda YU1, Jiangang GUO1, An’an WANG1, Jiajing LI1, Bei LIU2
Affiliations
  • 1the First Clinical Medical College of Lanzhou University, the First Hospital of Lanzhou University，Lanzhou，Gansu，China
  • 2Department of Hematology, the First Hospital of Lanzhou University，Lanzhou，Gansu，China
出版时间: 2025-09-30 doi: 10.16016/j.2097-0927.202507019
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摘要
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目的

探讨核仁磷酸蛋白1突变（nucleophosmin 1-mutated，NPM1m）的分型、变异等位基因频率（variant allele frequency，VAF）、共突变等对急性髓系白血病（acute myeloid leukemia，AML）患者预后的影响。

方法

回顾性分析2017年6月至2024年9月就诊于兰州大学第一医院血液科86例NPM1m-AML患者的临床资料及基因突变信息与生存情况，相关性分析采用Spearman相关系数，生存分析采用Kaplan-Meier曲线和Log-rank检验，使用Cox回归分析探究生存影响因素。

结果

NPM1m分型为罕见分型（Rares型）的患者总生存期（overall survival，OS）较ABD型缩短（中位OS：164天vs 416天，P=0.043）。NPM1m VAF值与初诊外周血白细胞计数、乳酸脱氢酶（lactate dehydrogenase，LDH）含量呈正相关（P<0.05），VAF≥0.37时OS缩短（中位OS：164天vs 730天，P=0.003）。合并骨髓增生异常相关基因（myelodysplasia-related gene，MR）突变较MR野生型预后差（中位OS：45天vs 395天，P<0.001）、FMS样酪氨酸激酶3内部串联重复（FMS-like tyrosine kinase 3-internal tandem duplication，FLT3-ITD）及DNMT3A三突变较非三突变预后差（中位OS：173 d vs 483 d，P=0.007）。合并PTPN11突变改善预后（中位OS：395 d vs 240 d，P=0.027），而合并N/KRAS突变较野生型患者呈现出预后更好的趋势（中位OS：662 d vs 189 d，P=0.070），但差异无统计学意义。多因素Cox分析显示LDH（HR=1.002，95%CI：1.000~1.003，P=0.005）、NPM1m VAF值（HR=2.415，95%CI：1.208~4.829，P=0.013）、Rares型（HR=3.037，95%CI：1.134~8.136，P=0.027）、MR突变（HR=5.283，95%CI：1.991~14.017，P<0.001）为患者OS相关的独立危险因素。

结论

NPM1m-AML的预后分层需结合NPM1m的分子异质性，Rares型、VAF≥0.37、合并FLT3-ITD及DNMT3A突变、MR突变是不良预后因素，合并PTPN11突变改善患者预后，合并N/KRAS显示出预后更好的趋势。LDH、NPM1m VAF值、Rares型、MR突变是影响NPM1m-AML患者OS的独立危险因素。

核仁磷酸蛋白1  /  急性髓系白血病  /  预后  /  危险因素
Objective

To investigate the impact of nucleophosmin 1-mutated (NPM1m) subtypes, variant allele frequency (VAF) and co-mutations on the survival outcomes of patients with acute myeloid leukemia (AML).

Methods

Clinical data, mutation status, and outcomes of 86 NPM1m-AML patients admitted in Department of Hematology, First Hospital of Lanzhou University between June 2017 and September 2024 were collected and retrospectively analyzed. Spearman correlation analysis, Kaplan-Meier curve analysis, Log-rank test, and Cox regression analysis was applied for correlation analysis, survival analysis, and factors affecting survival.

Results

The overall survival (OS) was significantly shorter in the Rares subtype of NPM1m than the ABD subtype (median OS: 164 d vs 416 d, P=0.043). The VAF of NPM1mwas positively correlated with the initial peripheral blood white blood cell count and lactate dehydrogenase (LDH) level (P<0.05). OS was reduced when VAF was ≥0.37 (median OS: 164 d vs 730 d, P=0.003). The presence of myelodysplasia-related gene (MR) mutations was associated with a poorer prognosis when compared to the MR wild-type (median OS: 45 d vs 395 d, P<0.001). The triple mutation of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and DNMT3A also indicated a worse prognosis than the non-triple mutation (median OS: 173 d vs 483 d, P=0.007). The presence of PTPN11 mutations was associated with improved OS (median OS: 395 d vs 240 d, P=0.027), while the patients with coexistence of N/KRAS mutations trended toward better prognosis than the wild-type patients (median OS: 662 d vs 189 d) though no statistical significance (P=0.070). Multivariate analysis revealed that LDH (HR=1.002, 95%CI: 1.000~1.003, P=0.005), NPM1m VAF (HR=2.415, 95%CI: 1.208~4.829, P=0.013), Rares subtype (HR=3.037, 95%CI: 1.134~8.136, P=0.027), and MR mutations (HR=5.283, 95%CI: 1.991~14.017, P<0.001) were independent risk factors associated with OS in the patients.

Conclusion

Molecular heterogeneity of NPM1m should be taken into account in prognostic stratification of NPM1m-AML. Factors including the Rares subtype, VAF≥0.37, coexistence of FLT3-ITD and DNMT3A mutations, and MR mutations are associated with poor prognosis of NPM1m-AML. The presence of PTPN11 mutations improves the prognosis, while the presence of N/KRAS mutations shows a trend toward better prognosis. LDH, NPM1m VAF, Rares subtype, and MR mutations are independent risk factors affecting OS of patients with NPM1m-AML.

nucleophosmin 1  /  acute myeloid leukemia  /  prognosis  /  risk factors
于晓达, 郭建刚, 王安安, 李佳璟, 刘蓓. 核仁磷酸蛋白1突变的分子异质性对急性髓系白血病预后的影响. 陆军军医大学学报, 2025 , 47 (18) : 2237 -2244 . DOI: 10.16016/j.2097-0927.202507019
Xiaoda YU, Jiangang GUO, An’an WANG, Jiajing LI, Bei LIU. Impact of molecular heterogeneity of NPM1 mutations on prognosis of acute myeloid leukemia: a clinical report of 86 cases[J]. Journal of Army Medical University, 2025 , 47 (18) : 2237 -2244 . DOI: 10.16016/j.2097-0927.202507019
正文
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急性髓系白血病（acute myeloid leukemia，AML）作为一种高度恶性的血液肿瘤，侵袭性高，病情进展迅速，预后差异通常由其遗传学特征决定，核仁磷酸蛋白1突变（nucleophosmin 1-mutated，NPM1m）是成人AML最常见的突变之一，发生率约为30%［1］。根据2022年欧洲白血病网络（European LeukmiaNet，ELN）风险分层，不伴有FMS样酪氨酸激酶3内部串联重复（FMS-like tyrosine kinase 3-internal tandem duplication，FLT3-ITD）突变的NPM1m-AML患者属于预后良好组，尽管骨髓增生异常相关基因（myelodysplasia-related gene，MR）突变的AML患者预后不良，但NPM1m-AML的良好预后不会因此受到影响［2］。除FLT3-ITD及MR突变外，其他高频共突变如DNMT3A、IDH1/2、RAS、WT1、PTPN11等也被指出会影响NPM1m-AML患者的预后，但结果尚存争议［3-4］。NPM1m根据插入核苷酸序列的不同分为A、B、D型和罕见分型（Rares型）共计140余种，其中A型插入序列TCTG，约占所有NPM1m-AML的75%~80%，B型插入序列CATG，约占10%，D型插入序列CCTG，约占5%，Rares型突变约占10%［5］。40%的NPM1m-AML患者初次治疗缓解后，后续仍会面临复发。既往研究中，年龄较大、Rares型、不良核型、较高的变异等位基因频率（variant allele frequency，VAF）、特定的共突变都会影响NPM1m-AML患者生存［6-8］。本研究回顾性分析86例NPM1m-AML患者的分子异质性及生存情况，拟探究此类患者的预后影响因素。
1　材料与方法
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1.1　病例资料
对2017年6月至2024年9月就诊于兰州大学第一医院血液科的86例NPM1m-AML初诊患者进行回顾性分析。纳入标准：符合世界卫生组织（World Health Organization，WHO）的AML诊断标准并通过基因检测确定存在NPM1突变。排除标准：①急性早幼粒细胞白血病；②关键临床资料缺失的患者。本研究经甘肃省兰州市兰州大学第一医院伦理委员会审核批准（伦理批号：LDYYLL2025-867）。
1.2　观察指标
患者初诊时的性别、年龄、FAB分型（French-American-British classification，FAB classification）、2022 ELN风险分层、染色体核型、外周白细胞计数、血红蛋白含量、血小板计数、血清乳酸脱氢酶（lactate dehydrogenase，LDH）含量、骨髓原始细胞比例、基因突变、NPM1m分型、NPM1m VAF、生存时间及状态等。
1.3　基因突变检测
采集3~5 mL新鲜骨髓标本，2017—2019年初诊的患者基因突变检测通过一代测序（sanger sequencing）技术检测，2019年之后的患者通过二代测序（next generation sequencing，NGS）技术检测。通过超声破碎法片段化核酸并构建文库，采用高效液相探针捕获目标序列，利用Illumina二代测序平台，对文库进行双末端（paired-end，PE）测序。
1.4　治疗方案
诱导治疗方案主要为去甲氧柔红霉素+阿糖胞苷/柔红霉素+阿糖胞苷（idarubicin+cytarabine/daunorubicin+ cytarabine，IA/DA）方案。对于化疗不耐受的患者采用维奈克拉+阿扎胞苷（venetoclax+azacitidine，VA）方案。存在FLT3-ITD突变的患者酌情联合FLT3抑制剂索拉非尼/吉瑞替尼。诱导化疗后达到完全缓解（complete response，CR）/完全缓解伴不完全血液学恢复（CR with incomplete blood count recovery，CRi）后依据预后分层及可测量残留疾病（measurable residual disease，MRD）动态监测进行巩固化疗或造血干细胞移植。
1.5　随访方式
通过电话对患者进行生存时间及状态随访，病例采集截止时间为2024年10月1日，随访截止时间为2025年1月1日。总生存期（overall survival，OS）为初诊确诊至死亡日期或随访截止日期。中位随访时间为1 049（520，1 712） d。
1.6　统计学分析
用SPSS 27.0软件分析相关数据。定量资料中符合正态分布或近似正态分布的数据以x¯±s表示，组间比较采用独立样本t检验；不符合正态分布的定量资料以M（P25，P75）表示，组间比较采用非参数秩和检验。定性资料以例（%）表示，组间比较采用χ2检验。相关性分析采用Spearman相关系数。生存分析采用Kaplan-Meier曲线和Log-rank检验。采用Cox回归分析探究影响预后的独立危险因素。采用R 4.3.2绘图。P<0.05为差异具有统计学意义。
2　结果
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2.1　基线资料
本研究共纳入86例NPM1m-AML患者，其中男性44例（51.16%），女性42例（48.84%），平均年龄（56.26±14.01）岁，FAB分型常见M5型35例（40.70%），M2型25例（29.07%），M4型14例（16.27%），M1型6例（6.98%），未确定分型6例（6.98%）。正常核型78例（90.70%），异常核型8例（9.30%）。根据2022 ELN风险分层，预后良好45例（52.32%），预后中等35例（40.70%），预后不良6例（6.98%）。初诊外周血白细胞计数中位值27.16×109/L，血红蛋白含量平均值（80.48±23.28）g/L，血小板计数中位值53.00×109/L。血清LDH含量中位值458.00 U/L。初诊骨髓原始细胞比例中位值62.75%。根据NPM1m分型（n=82）及NPM1m VAF值（n=67）将患者分组，基线资料见表1。
2.2　 NPM1m不同分型特征及对预后的影响
86例患者中，可用于评估分型的患者82例，其中A型64例（78%），B型2例（2%），D型3例（4%），非ABD组为罕见分型（Rares型）共13例（16%）。ABD组（n=69）与Rares组（n=13）相比，初诊外周血白细胞计数更高（中位值34.66×10⁹/L vs 4.75×10⁹/L，P=0.035），而年龄、性别、血小板计数、血红蛋白浓度、骨髓原始细胞比例差异均无统计学意义。DNMT3A突变在ABD组发生率更高（42.03% vs 7.69%，P=0.018），其他表观遗传调控基因（IDH1、IDH2、TET2、ASXL1等）或细胞信号转导基因（FLT3-ITD、FLT3-TKD、NRAS、WT1、PTPN11等）突变发生率的差异无统计学意义（表1）。虽然既往研究中不同的NPM1m分型对AML预后的影响尚未达成一致，但本研究发现，Rares组的OS较ABD组缩短（中位OS：164 d vs 416 d，P=0.043，图1A）。同时，在≥60岁的38例患者中，Rares组患者（n=6）较ABD组患者（n=32）表现出更差的预后，OS显著缩短（中位OS：105 d vs 416 d，P=0.013，图1B）。
2.3　 NPM1mVAF值及对预后的影响
对具有VAF数据的67例患者进行相关性分析，发现NPM1突变的VAF值与初诊外周血白细胞计数（r=0.261，P=0.033）、LDH（r=0.343，P=0.005）呈正相关，与骨髓原始细胞比例相关性无统计学意义（r=0.076，P=0.539，图2A）。VAF值的中位数为0.37，以该值为界将患者分为2组进行分析，FLT3-ITD突变（60.61% vs 41.18%，P=0.112）和DNMT3A突变（54.55% vs 32.35%，P=0.067）在VAF值较高时发生频率更高，但差异无统计学意义（表1）。与VAF<0.37组相比，VAF≥0.37组OS显著缩短（中位OS：164 d vs 730 d，P=0.003，图2B）。VAF≥0.37在≥60岁的患者中OS显著缩短（中位OS：164 d vs 730 d，P=0.012，图2C）。突变亚组中分析，合并FLT3-ITD突变患者如VAF≥0.37，OS明显缩短（中位OS：123 d vs 623 d，P=0.011，图2D）。
2.4　 NPM1m共突变特征及对预后的影响
2.4.1　 NPM1m-AML共突变图谱
对86例患者进行基因检测，除NPM1外，共有31种基因突变被检测到，常见共突变基因包括FLT3-ITD（48%）、DNMT3A（37%）、IDH2（23%）、WT1（19%）、NRAS（17%）、IDH1（14%）、FLT3-TKD（13%）、PTPN11（9%），仅存在NPM1突变的患者仅占2%。按功能分类，表观遗传调控基因突变最常见，其次是细胞信号转导基因突变（图3A）。在NPM1m-AML患者中，对突变发生率≥3%的基因进行相互作用分析，发现FLT3-ITD与NRAS（r=-0.320，P<0.01）、PTPN11（r=-0.226，P<0.05）显著突变互斥，ASXL1与KRAS（r=0.213，P<0.05）、CEBPA（r=0.417，P<0.001）、TET2（r=0.373，P<0.001）显著突变共存，PTPN11与IDH1（r=0.330，P<0.01）、NRAS（r=0.380，P<0.001）、KRAS（r=0.310，P<0.01）显著突变共存（图3B）。
2.4.2　 NPM1与FLT3-ITD共突变
FLT3-ITD突变是NPM1m-AML最常见的共存突变，对41例双突变患者的临床特征及预后进行分析，此类患者表现为较高的初诊外周血白细胞计数（P=0.014），FLT3-ITD突变的患者OS较FLT3-ITD野生型的患者缩短（中位OS：209 d vs 498 d，P=0.101，图4A），但差异无统计学意义。NPM1合并FLT3-ITD及DNMT3A为AML常见三突变，本组患者共17例存在三突变（19%，17/86），中位OS为173天，非三突变患者中位OS为483天，三突变患者预后较差且差异具有统计学意义（P=0.007，图4B）。
2.4.3　 NPM1与其他基因共突变
尽管2022 ELN将合并MR突变的NPM1m-AML患者定义为预后良好组，但NPM1m-AML患者的生存是否受MR影响仍存在争议，回顾分析12例存在MR突变的NPM1m-AML患者，发现合并MR突变的患者较MR野生型的OS显著缩短（中位OS：45 d vs 395 d，P<0.001，图4C）。此外，N/KRAS突变较N/KRAS野生型可延长NPM1m-AML的OS（中位OS：662天vs 189天，P=0.070，图4D），PTPN11突变延长NPM1m-AML的OS，差异具有统计学意义（中位OS：395 d vs 240 d，P=0.027，图4E）。
2.5　 NPM1m-AML患者OS的Cox回归分析
为进一步明确NPM1m-AML患者OS的影 响因素，对86例患者的临床资料进行单因素Cox回归分析，结果显示白细胞计数、血小板、LDH、NPM1m VAF值、Rares型、DNMT3A突变、PTPN11突变、N/KRAS突变、MR突变与患者OS相关（P<0.1，表2），将以上因素纳入多因素分析，发现LDH、VAF、Rares型、MR突变为患者OS相关的独立危险因素（P<0.05，表3）。
3　讨论
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NPM1突变占成人AML的30%，是发生率最高的突变之一，在2022ELN中，不伴FLT3-ITD的NPM1m-AML被列为预后良好组［2］。然而，NPM1m-AML异质性较强，研究发现NPM1m-AML的预后可能受到年龄、预后不良核型、NPM1m分型、NPM1m VAF、共突变等的影响，预后因素较为复杂［6-9］。本研究发现NPM1m分型、NPM1m VAF、共突变与NPM1m-AML预后相关。
3.1　Rares型是NPM1m-AML不良预后的指标
NPM1m分型与临床特征的相关性及其对预后的影响在国外研究中已有报道，OTHMAN等［8］在一项大样本研究中证实，Rares型NPM1m-AML患者的OS更短，MRD阴性率更低，复发或死亡风险较高，PASTORE等［10］认为NPM1m分型对细胞遗传学正常的AML生存无影响。本研究中，Rares型突变患者的DNMT3A突变发生率低，初诊外周血白细胞计数较低，OS缩短，与国外研究结果一致［8，11-12］。对于不同分型导致预后差异的原因需要进一步探索，可能的原因包括不同的发病机制、不同的核输出序列与蛋白定位［8，12］。因此，Rares型未来有望纳入AML的预后分层标准。
3.2　 NPM1m VAF值与肿瘤负荷及生存风险密切相关
NPM1m VAF值与特定的临床特征相关，其对预后的影响存在一定争议。PATEL等［7］证实NPM1m VAF值与初诊外周血白细胞计数、外周血原始细胞比例、骨髓原始细胞比例呈正相关，NPM1m VAF≥0.44的患者OS与无事件生存期（Event-Free Survival，EFS）缩短，但也有研究认为NPM1m VAF对OS、EFS无显著影响［13］。导致结果差异的原因可能与诱导方案、造血干细胞移植率及FLT3抑制剂使用率有关。本研究中NPM1m VAF值与初诊外周血白细胞计数、LDH呈正相关，表明VAF与AML肿瘤负荷相关。以NPM1m VAF值中位数为截断值生存分析显示，VAF≥0.37时OS缩短。因此，为了实现NPM1m-AML患者精准的预后分层，未来可以考虑将NPM1m VAF值纳入预后分层。
3.3　合并基因突变影响NPM1m-AML预后
此外，NPM1突变常合并其他基因突变，研究发现FLT3-ITD、DNMT3A、IDH1/2、NRAS等突变会影响NPM1m-AML的预后，尤其合并FLT3-ITD、DNMT3A三突变时预后极差。GNG4作为三突变的差异表达基因，可能与预后差的潜在机制相关［14］。本研究发现，合并MR、PTPN11突变对NPM1m-AML预后也存在影响，N/KRAS突变虽有改善预后的趋势，但因单中心样本量有限，差异未达统计学意义，结果仍需通过多中心大样本研究进一步验证。
3.4　LDH、NPM1m VAF值、Rares型、MR突变为OS的独立危险因素
多因素Cox回归分析发现LDH、NPM1m VAF值、Rares型、MR突变为患者OS的独立危险因素，LDH反映肿瘤细胞的代谢活性，可能作为判断NPM1m-AML不良预后的指标；较高的NPM1m VAF值与肿瘤负荷相关且独立影响生存，为划分高危患者提供依据；Rares型作为OS的独立危险因素，存在纳入预后分层标准的可能，但仍需大样本研究的验证；同时，MR突变在NPM1m-AML风险评估中的作用也不可忽视。
综上所述，NPM1m-AML患者的临床特征与预后受NPM1m分型、NPM1m VAF值和共突变基因的影响，进行预后分层时应充分考虑到NPM1突变的分子异质性，以更精准地评估患者风险并制定个体化治疗策略。未来需要大样本的研究明确NPM1突变的分子异质性对患者预后的影响。

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2025年第47卷第18期
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doi: 10.16016/j.2097-0927.202507019
  • 接收时间：2025-07-05
  • 首发时间：2026-10-28
  • 出版时间：2025-09-30
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  • 收稿日期：2025-07-05
  • 修回日期：2025-08-06
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    1兰州大学：第一临床医学院，甘肃 兰州
    2兰州大学：第一医院血液科，甘肃 兰州

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