CEBPA bZIP框内突变在急性髓系白血病中的研究进展

doi:10.20223/j.cnki.1000-8535.2025.02.001

摘要/Abstract

摘要： CCAAT增强子结合蛋白A（CEBPA）是调节血液发育过程中髓系分化和造血干祖细胞活性的关键转录因子之一。CEBPA基因突变常见于急性髓系白血病（AML）中,最近研究表明CEBPA bZIP框内单位点和经典双等位基因突变AML患者均具有类似的临床特征,已被单独划分为AML亚群。CEBPA bZIP框内突变而非传统的双等位CEBPA基因突变成为AML良好预后的分子指标,表明其在AML疾病进展和治疗预后中的重要性和特殊性。本文将从CEBPA蛋白在血液系统中的功能、CEBPA bZIP框内突变AML的临床特征与分子作用机制、以及伴CEBPA突变AML的治疗现状等方面进行综述,为进一步研究CEBPA bZIP框内突变在AML中的致病性和精准治疗新药物开发提供参考。

关键词: 急性髓系白血病, CCAAT增强子结合蛋白A, bZIP框内突变

Abstract: CCAAT enhancer-binding protein A（CEBPA）is one of the key transcription factors regulating myeloid differentiation and hematopoietic stem/progenitor cell maintenance during hematopoiesis．CEBPA gene mutations are commonly found in acute myeloid leukemia（AML）．Recent studies have demonstrated that AML patients haboring single CEBPA bZIP in-frame mutations or classical bi-allelic CEBPA mutations show similar clinical features and it has been individually classified as AML subgroup．Additionally,it is CEBPA bZIP in-frame mutations rather than the traditional biallelic CEBPA mutations that have emerged as a molecular indicator of favorable prognosis for clinical AML management,suggesting its importance and specificity in AML disease progression and therapeutic prognosis．Here,we reviewed serval aspects including the hematopoietic function of CEBPA protein,the clinical features and molecular mechanisms of AML with CEBPA bZIP in-frame mutations,and the current status of the treatment of AML with CEBPA mutations,which will provide a reference for further study of the pathogenicity of CEBPA bZIP in-frame mutations in AML and the development of new drugs for precision therapy．

Key words: acute myeloid leukemia, CCAAT enhancer-binding protein A, bZIP in-frame mutations

陈克敏, 黄志斌, 王顺清, 张文清. CEBPA bZIP框内突变在急性髓系白血病中的研究进展[J]. 广州医药, 2025, 56(2): 139-150.

CHEN Kemin, HUANG Zhibin, WANG Shunqing, ZHANG Wenqing. Research progress on CEBPA bZIP in-frame mutations in acute myeloid leukemia[J]. Guangzhou Medical Journal, 2025, 56(2): 139-150.

参考文献

[1] SHORT N J,RYTTING M E,CORTES J E.Acute myeloid leukaemia[J].Lancet,2018,392(10147):593-606.
[2] SHALLIS R M,WANG R,DAVIDOFF A,et al.Epidemiology of acute myeloid leukemia:Recent progress and enduring challenges[J].Blood Rev,2019(36):70-87.
[3] NEWELL L F,COOK R J.Advances in acute myeloid leukemia[J].BMJ,2021(375):n2026.
[4] BHANSALI R S,PRATZ K W,LAI C.Recent advances in targeted therapies in acute myeloid leukemia[J].J Hematol Oncol,2023,16(1):29.
[5] YANG X,WANG J.Precision therapy for acute myeloid leukemia[J].J Hematol Oncol,2018,11(1):3.
[6] NIE Y,SU L,LI W,et al.Novel insights of acute myeloid leukemia with CEBPA deregulation:Heterogeneity dissection and re-stratification[J].Crit Rev Oncol Hematol,2021(163):103379.
[7] SU L,GAO S J,LIU X L,et al.CEBPA mutations in patients with de novo acute myeloid leukemia:data analysis in a Chinese population[J].Onco Targets Ther,2016(9):3399-3403.
[8] SCHMIDT L,HEYES E,GREBIEN F.Gain-of-Function Effects of N-Terminal CEBPA Mutations in Acute Myeloid Leukemia[J].Bioessays,2020,42(2):e1900178.
[9] WOUTERS B J,LÖWENBERG B,ERPELINCK-VERSCHUEREN C A J,et al.Double CEBPA mutations,but not single CEBPA mutations,define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome[J].Blood,2009,113(13):3088-3091.
[10] WILHELMSON A S,PORSE B T.CCAAT enhancer binding protein alpha(CEBPA)biallelic acute myeloid leukaemia:cooperating lesions,molecular mechanisms and clinical relevance[J].Br J Haematol,2020,190(4):495-507.
[11] ARBER D A,ORAZI A,HASSERJIAN R,et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia[J].Blood,2016,127(20):2391-2405.
[12] WAKITA S,SAKAGUCHI M,OH I,et al.Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia[J].Blood Adv,2022,6(1):238-247.
[13] HUBER S,BAER C,HUTTER S,et al.AML classification in the year 2023:How to avoid a Babylonian confusion of languages[J].Leukemia,2023,37(7):1413-1420.
[14] FRIEDMAN A D.C/EBPα in normal and malignant myelopoiesis[J].Int J Hematol,2015,101(4):330-341.
[15] IN K,ZAINI M A,MÜLLER C,et al.Shwachman-Bodian-Diamond syndrome(SBDS)protein deficiency impairs translation re-initiation from C/EBPα and C/EBPβ mRNAs[J].Nucleic Acids Res,2016,44(9):4134-4146.
[16] MILLER M,SHUMAN J D,SEBASTIAN T,et al.Structural basis for DNA recognition by the basic region leucine zipper transcription factor CCAAT/enhancer-binding protein α[J].J Biol Chem,2003,278(17):15178-15184.
[17] RAMJI DP,FOKA P.CCAAT/enhancer-binding proteins:structure,function and regulation[J].Biochem J,2002,365(Pt 3):561-575.
[18] GARCIA-CUELLAR M P,AKAN S,SLANY R K.A C/ebpα isoform specific differentiation program in immortalized myelocytes[J].Leukemia,2023,37(9):1850-1859.
[19] VINSON C R,HAI T,BOYD S M.Dimerization specificity of the leucine zipper-containing bZIP motif on DNA binding:prediction and rational design[J].Genes Dev,1993,7(6):1047-1058.
[20] ZHANG D E,ZHANG P,WANG N D,et al.Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein α-deficient mice[J].Proc Natl Acad Sci U S A,1997,94(2):569-574.
[21] SCHUSTER M B,FRANK A K,BAGGER F O,et al.Lack of the p42 form of C/EBPα leads to spontaneous immortalization and lineage infidelity of committed myeloid progenitors[J].Exp Hematol,2013,41(10):882-893.e16.
[22] ZHANG P,IWASAKI-ARAI J,IWASAKI H,et al.Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBPα[J].Immunity,2004,21(6):853-863.
[23] DAI Y M,ZHU L,HUANG Z B,et al.Cebpα is essential for the embryonic myeloid progenitor and neutrophil maintenance in zebrafish[J].J Genet Genomics,2016,43(10):593-600.
[24] OHLSSON E,SCHUSTER M B,HASEMANN M,et al.The multifaceted functions of C/EBPα in normal and malignant haematopoiesis[J].Leukemia,2016,30(4):767-775.
[25] AVELLINO R,DELWEL R.Expression and regulation of C/EBPα in normal myelopoiesis and in malignant transformation[J].Blood,2017,129(15):2083-2091.
[26] JOHNSON P F.Molecular stop signs:regulation of cell-cycle arrest by C/EBP transcription factors[J].J Cell Sci,2005,118(Pt 12):2545-2555.
[27] YUAN H,GAO S,CHEN H,et al.Primitive macrophages are dispensable for HSPC mobilization and definitive hematopoiesis[J].Blood,2019,134(9):782-784.
[28] CHEN K M,WU J Y,ZHANG Y X,et al.Cebpa is required for haematopoietic stem and progenitor cell generation and maintenance in zebrafish[J].Open Biol,2024,14(11):240215.
[29] LIN L I,CHEN C Y,LIN D T,et al.Characterization of CEBPA mutations in acute myeloid leukemia:most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells[J].Clin Cancer Res,2005,11(4):1372-1379.
[30] BULLINGER L.CEBPA mutations in AML:site matters[J].Blood,2022,139(1):6-7.
[31] TAUBE F,GEORGI J A,KRAMER M,et al.CEBPA mutations in 4708 patients with acute myeloid leukemia:differential impact of bZIP and TAD mutations on outcome[J].Blood,2022,139(1):87-103.
[32] SU L,TAN Y H,LIN H,et al.Mutational spectrum of acute myeloid leukemia patients with double CEBPA mutations based on next-generation sequencing and its prognostic significance[J].Oncotarget,2018,9(38):24970-24979.
[33] PABST T,MUELLER B U,ZHANG P,et al.Dominant-negative mutations of CEBPA,encoding CCAAT/enhancer binding protein-α(C/EBPα),in acute myeloid leukemia[J].Nat Genet,2001,27(3):263-270.
[34] TARLOCK K,LAMBLE A,WANG J,et al.CEBPA bZIP mutations are associated with favorable prognosis in de novo AML:a report from the children's oncology group[J].Blood,2021,138(13):1137-1147.
[35] AHN S Y,KIM T H,KIM M,et al.Clinical significance of bZIP in-frame CEBPA-mutated normal karyotype acute myeloid leukemia[J].Cancer Res Treat,2023,55(3):1011-1022.
[36] ZHANG F,SHEN Z,XIE J,et al.CEBPA bZIP in-frame mutations in acute myeloid leukemia:prognostic and therapeutic implications[J].Blood Cancer J,2024,14(1):59.
[37] GEORGI J A,STASIK S,KRAMER M,et al.Prognostic impact of CEBPA mutational subgroups in adult AML[J].Leukemia,2024,38(2):281-290.
[38] YE M,ZHANG H,YANG H,et al.Hematopoietic differentiation is required for initiation of acute myeloid leukemia[J].Cell Stem Cell,2015,17(5):611-623.
[39] RAMBERGER E,SAPOZHNIKOVA V,KOWENZ-LEUTZ E,et al.PRISMA and BioID disclose a motifs-based interactome of the intrinsically disordered transcription factor C/EBPα[J].iScience,2021,24(6):102686.
[40] GELETU M,BALKHI M Y,PEER ZADA A A,et al.Target proteins of C/EBPalphap30 in AML:C/EBPalphap30 enhances sumoylation of C/EBPalphap42 via up-regulation of Ubc9[J].Blood,2007,110(9):3301-3309.
[41] JAKOBSEN J S,LAURSEN L G,SCHUSTER M B,et al.Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML[J].Sci Adv,2019,5(7):eaaw4304.
[42] HEYES E,SCHMIDT L,MANHART G,et al.Identification of gene targets of mutant C/EBPα reveals a critical role for MSI2 in CEBPA-mutated AML[J].Leukemia,2021,35(9):2526-2538.
[43] PORSE B T,PEDERSEN T Å,XU X,et al.E2F repression by C/EBPα is required for adipogenesis and granulopoiesis in vivo[J].Cell,2001,107(2):247-258.
[44] PORSE B T,BRYDER D,THEILGAARD-MÖNCH K,et al.Loss of C/EBPα cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage[J].J Exp Med,2005,202(1):85-96.
[45] GOMBART A F,HOFMANN W K,KAWANO S,et al.Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias[J].Blood,2002,99(4):1332-1340.
[46] TOGAMI K,KITAURA J,UCHIDA T,et al.A C-terminal mutant of CCAAT-enhancer-binding protein α(C/EBPα-Cm)downregulates Csf1r,a potent accelerator in the progression of acute myeloid leukemia with C/EBPα-Cm[J].Exp Hematol,2015,43(4):300-308.
[47] BERESHCHENKO O,MANCINI E,MOORE S,et al.Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPα mutant AML[J].Cancer Cell,2009,16(5):390-400.
[48] GENTLE I E,MOELTER I,BADR M T,et al.The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression[J].Cell Death Dis,2021,12(7):675.
[49] BARARIA D,KWOK H S,WELNER R S,et al.Acetylation of C/EBPα inhibits its granulopoietic function[J].Nat Commun,2016(7):10968.
[50] CHEN X,ZHOU W,SONG R H,et al.Tumor suppressor CEBPA interacts with and inhibits DNMT3A activity[J].Sci Adv,2022,8(4):eabl5220.
[51] WANG D,SUN T,XIA Y,et al.Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation[J].Nat Commun,2023,14(1):6907.
[52] ROWE J M.The “7+3” regimen in acute myeloid leukemia[J].Haematologica,2022,107(1):3.
[53] FORSBERG M,KONOPLEVA M.AML treatment:conventional chemotherapy and emerging novel agents[J].Trends Pharmacol Sci,2024,45(5):430-448.
[54] KUROSAWA S,YAMAGUCHI H,YAMAGUCHI T,et al.The prognostic impact of FLT3-ITD,NPM1 and CEBPa in cytogenetically intermediate-risk AML after first relapse[J].Int J Hematol,2020,112(2):200-209.
[55] AHN J S,KIM J Y,KIM H J,et al.Normal karyotype acute myeloid leukemia patients with CEBPA double mutation have a favorable prognosis but no survival benefit from allogeneic stem cell transplant[J].Ann Hematol,2016,95(2):301-310.
[56] SU L,GAO S J,TAN Y H,et al.CSF3R mutations were associated with an unfavorable prognosis in patients with acute myeloid leukemia with CEBPA double mutations[J].Ann Hematol,2019,98(7):1641-1646.
[57] TIEN F M,YAO C Y,TSAI X C H,et al.Dysregulated immune and metabolic pathways are associated with poor survival in adult acute myeloid leukemia with CEBPA bZIP in-frame mutations[J].Blood Cancer J,2024,14(1):15.
[58] WANG J,LU R Q,WU Y,et al.Detection of measurable residual disease may better predict outcomes than mutations based on next-generation sequencing in acute myeloid leukaemia with biallelic mutations of CEBPA[J].Br J Haematol,2020,190(4):533-544.
[59] WANG J,JIANG H,JING Y,et al.Prognostic implications of the detection of measurable residual disease and mutations based on next-generation sequencing in acute myeloid leukaemia with biallelic mutations of CEBPA[J].Br J Haematol,2022,198(1):e3-e8.
[60] DÖHNER H,WEI A H,APPELBAUM F R,et al.Diagnosis and management of AML in adults:2022 recommendations from an international expert panel on behalf of the ELN[J].Blood,2022,140(12):1345-1377.
[61] ARSLAN S,ZHANG J,DHAKAL P,et al.Outcomes of therapy with venetoclax combined with a hypomethylating agent in favorable-risk acute myeloid leukemia[J].Am J Hematol,2021,96(3):E59-E63.
[62] ZHANG H,ALBERICH-JORDA M,AMABILE G,et al.Sox4 is a key oncogenic target in C/EBPα mutant acute myeloid leukemia[J].Cancer Cell,2013,24(5):575-588.
[63] SCHMIDT L,HEYES E,SCHEIBLECKER L,et al.CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex[J].Leukemia,2019,33(7):1608-1619.
[64] LAVALÍ V-P,KROSL J,LEMIEUX S,et al.Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors[J].Blood,2016,127(24):3054-3061.
[65] BRAUN T P,COBLENTZ C,DANIEL J COLEMAN B M,et al.Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia[J].Proc Natl Acad Sci U S A,2020,117(24):13670-13679.
[66] LO-COCO F,AVVISATI G,VIGNETTI M,et al.Retinoic acid and arsenic trioxide for acute promyelocytic leukemia[J].N Engl J Med,2013,369(2):111-121.
[67] NI X,HU G,CAI X.The success and the challenge of all-trans retinoic acid in the treatment of cancer[J].Crit Rev Food Sci Nutr,2019,59(sup1):S71-S80.
[68] NGUYEN C H,GRANDITS A M,PURTON L E,et al.All-trans retinoic acid in non-promyelocytic acute myeloid leukemia:driver lesion dependent effects on leukemic stem cells[J].Cell Cycle,2020,19(20):2573-2588.
[69] SNADDON J,SMITH M L,NEAT M,et al.Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2[J].Genes Chromosomes Cancer,2003,37(1):72-78.
[70] VERGEZ F,LARGEAUD L,BERTOLI S,et al.Phenotypically-defined stages of leukemia arrest predict main driver mutations subgroups,and outcome in acute myeloid leukemia[J].Blood Cancer J,2022,12(8):117.
[71] ADAMO A,CHIN P,KEANE P,et al.Identification and interrogation of the gene regulatory network of CEBPA-double mutant acute myeloid leukemia[J].Leukemia,2023,37(1):102-112.
[72] LISS A,OOI C H,ZJABLOVSKAJA P,et al.The gene signature in CCAAT-enhancer-binding protein α dysfunctional acute myeloid leukemia predicts responsiveness to histone deacetylase inhibitors[J].Haematologica,2014,99(4):697-705.