# Myelodysplastic syndrome progress to acute myeloid leukemia: new insights and updates **Authors:** Yucheng Zhang, Lixiang Yan, Chenyang Fan, Bofan Zhao, Meng Chen, Xiaogang Hao, Gengda Zhu, Yanan Jia, Yajing Xu, Zhexin Shi PMC · DOI: 10.3389/fimmu.2026.1769944 · Frontiers in Immunology · 2026-02-04 ## TL;DR This paper reviews how myelodysplastic syndromes progress to leukemia, focusing on genetic changes and treatment strategies. ## Contribution The paper provides new insights into the molecular mechanisms driving MDS progression to AML and their clinical implications. ## Key findings - MDS progression to sAML involves genetic and environmental interactions promoting clonal selection. - Single-cell technologies reveal heterogeneity in MDS stem cells and their niche. - Understanding these mechanisms can improve risk stratification and treatment strategies. ## Abstract The progression of myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (sAML), classified under AML with myelodysplasia-related changes (AML-MRC), is a multi-step process driven by the dynamic interplay between cell-intrinsic genetic events and extrinsic microenvironmental remodeling. In this review, we discuss how these changes foster clonal selection and leukemic transformation. Emerging insights from single-cell technologies are highlighted, revealing the dynamic heterogeneity of MDS stem cells and their niche. Finally, we discussed the clinical implications of these mechanisms, including their impact on risk stratification, therapy failure (particularly after hypomethylating agents), and the development of novel treatment strategies aimed at intercepting progression. Integrating molecular findings with clinical translation is essential for improving outcomes in this high-risk disease continuum. ## Linked entities - **Diseases:** myelodysplastic syndromes (MONDO:0018881), acute myeloid leukemia (MONDO:0015667) ## Full-text entities - **Genes:** HAVCR2 (hepatitis A virus cellular receptor 2) [NCBI Gene 84868] {aka CD366, HAVcr-2, KIM-3, SPTCL, TIM3, TIMD-3}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, NGF (nerve growth factor) [NCBI Gene 4803] {aka Beta-NGF, HSAN5, NGFB}, U2AF1 (U2 small nuclear RNA auxiliary factor 1) [NCBI Gene 7307] {aka FP793, RN, RNU2AF1, U2AF35, U2AFBP}, PINK1 (PTEN induced kinase 1) [NCBI Gene 65018] {aka BRPK, PARK6}, CD38 (CD38 molecule) [NCBI Gene 952] {aka ADPRC 1, ADPRC1, cADPR1}, HOXB7 (homeobox B7) [NCBI Gene 3217] {aka HHO.C1, HOX2, HOX2C, Hox-2.3}, CEACAM1 (CEA cell adhesion molecule 1) [NCBI Gene 634] {aka BGP, BGP1, BGPI}, DNM1L (dynamin 1 like) [NCBI Gene 10059] {aka DLP1, DRP1, DVLP, DYMPLE, EMPF, EMPF1}, PLK1 (polo like kinase 1) [NCBI Gene 5347] {aka PLK, STPK13}, GATA2 (GATA binding protein 2) [NCBI Gene 2624] {aka DCML, IMD21, MONOMAC, NFE1B}, TET2 (tet methylcytosine dioxygenase 2) [NCBI Gene 54790] {aka IMD75, KIAA1546, MDS}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, CEBPA (CCAAT enhancer binding protein alpha) [NCBI Gene 1050] {aka C/EBP-alpha, CEBP}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, HLA-DRA (major histocompatibility complex, class II, DR alpha) [NCBI Gene 3122] {aka HLA-DRA1}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, ELF1 (E74 like ETS transcription factor 1) [NCBI Gene 1997] {aka EFTUD1, RIA1}, MYC (MYC proto-oncogene, bHLH transcription factor) [NCBI Gene 4609] {aka MRTL, MYCC, bHLHe39, c-Myc}, CPT1A (carnitine palmitoyltransferase 1A) [NCBI Gene 1374] {aka CPT I, CPT1, CPT1-L, CPTI-L, L-CPT1}, POT1 (protection of telomeres 1) [NCBI Gene 25913] {aka CMM10, CRMCC3, GLM9, HPOT1, PFBMFT8, TPDS3}, SRSF2 (serine and arginine rich splicing factor 2) [NCBI Gene 6427] {aka PR264, SC-35, SC35, SFRS2, SFRS2A, SRp30b}, IL18 (interleukin 18) [NCBI Gene 3606] {aka IGIF, IL-18, IL-1g, IL1F4}, DNMT3A (DNA methyltransferase 3 alpha) [NCBI Gene 1788] {aka DNMT3A2, HESJAS, M.HsaIIIA, TBRS}, RUNX1 (RUNX family transcription factor 1) [NCBI Gene 861] {aka AML1, AML1-EVI-1, AMLCR1, CBF2alpha, CBFA2, EVI-1}, CD34 (CD34 molecule) [NCBI Gene 947], CCL3 (C-C motif chemokine ligand 3) [NCBI Gene 6348] {aka G0S19-1, LD78, LD78ALPHA, MIP-1-alpha, MIP1A, SCI}, IL2RA (interleukin 2 receptor subunit alpha) [NCBI Gene 3559] {aka CD25, IDDM10, IL2R, IMD41, TCGFR, p55}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, HOXB3 (homeobox B3) [NCBI Gene 3213] {aka HOX2, HOX2G, Hox-2.7}, LGALS9 (galectin 9) [NCBI Gene 3965] {aka HUAT, LGALS9A}, TNFRSF9 (TNF receptor superfamily member 9) [NCBI Gene 3604] {aka 4-1BB, CD137, CDw137, ILA, IMD109}, CD200 (CD200 molecule) [NCBI Gene 4345] {aka MOX1, MOX2, MRC, OX-2}, MAP2K7 (mitogen-activated protein kinase kinase 7) [NCBI Gene 5609] {aka JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) [NCBI Gene 2146] {aka ENX-1, ENX1, EZH2b, KMT6, KMT6A, WVS}, MAML3 (mastermind like transcriptional coactivator 3) [NCBI Gene 55534] {aka CAGH3, ERDA3, GDN, MAM-2, MAM2, TNRC3}, IL12B (interleukin 12B) [NCBI Gene 3593] {aka CLMF, CLMF2, IL-12B, IMD28, IMD29, NKSF}, PLCB1 (phospholipase C beta 1) [NCBI Gene 23236] {aka DEE12, EIEE12, PI-PLC, PLC-154, PLC-I, PLC-beta-1}, CD69 (CD69 molecule) [NCBI Gene 969] {aka AIM, BL-AC/P26, CLEC2C, EA1, GP32/28, MLR-3}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, TOPORS (TOP1 binding arginine/serine rich protein, E3 ubiquitin ligase) [NCBI Gene 10210] {aka LUN, P53BP3, RP31, TP53BPL}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, BCL2 (BCL2 apoptosis regulator) [NCBI Gene 596] {aka Bcl-2, PPP1R50}, ASXL1 (ASXL transcriptional regulator 1) [NCBI Gene 171023] {aka BOPS, MDS}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, SF3B1 (splicing factor 3b subunit 1) [NCBI Gene 23451] {aka Hsh155, MDS, PRP10, PRPF10, SAP155, SF3b155}, CASP8 (caspase 8) [NCBI Gene 841] {aka ALPS2B, CAP4, Casp-8, FLICE, MACH, MCH5}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, TRIM69 (tripartite motif containing 69) [NCBI Gene 140691] {aka HSD-34, HSD34, RNF36, Trif}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, CD86 (CD86 molecule) [NCBI Gene 942] {aka B7-2, B7.2, B70, BU63, CD28LG2, CD86 v6}, KMT2A (lysine methyltransferase 2A) [NCBI Gene 4297] {aka ALL-1, ALL1, CXXC7, GAS7, HRX, HTRX}, DNMT1 (DNA methyltransferase 1) [NCBI Gene 1786] {aka ADCADN, AIM, CXXC9, DNMT, HSN1E, MCMT}, MIR146A (microRNA 146a) [NCBI Gene 406938] {aka MIRN146, MIRN146A, miR-146a, miRNA146A}, IL9 (interleukin 9) [NCBI Gene 3578] {aka HP40, IL-9, P40}, NPM1 (nucleophosmin 1) [NCBI Gene 4869] {aka B23, NPM} - **Diseases:** myelodysplasia-related changes (MESH:D009402), HMAF (MESH:D051437), Cancer (MESH:D009369), diabetes (MESH:D003920), Mitochondrial dysfunction (MESH:D028361), Chronic inflammation (MESH:D007249), CH (MESH:C536227), IOL (MESH:D019190), bone marrow failure (MESH:D000080983), dysplastic (MESH:D004416), hypoxia (MESH:D000860), Myelodysplasia (MESH:D009436), metabolic (MESH:D008659), genetic abnormalities (MESH:D030342), metabolic dysregulation (MESH:D021081), AML- (MESH:D015470), clonal disorders (MESH:C580365), hematological malignancies (MESH:D019337), LR-MDS (MESH:D009190), obesity (MESH:D009765), hypoxic (MESH:D002534), autoimmune conditions (MESH:D001327), infection (MESH:D007239), Immune (MESH:D007154), BMME (MESH:D001855), HR (MESH:D002303), ALL (MESH:D054198), cytopenias (MESH:D006402), leukemic (MESH:D007938), mitochondrial defects (MESH:C565376), OS (MESH:D000079225), chromosomal (MESH:D025063), long telomere syndromes (MESH:D000094024), trisomy 8 (MESH:C537942), immune dysregulation (OMIM:614878), aplastic anemia (MESH:D000741), LSCs (MESH:D015458) - **Chemicals:** Venetoclax (MESH:C579720), sabatolimab (MESH:C000723550), idarubicin (MESH:D015255), molecular oxygen (MESH:D010100), decitabine (MESH:D000077209), eltrombopag (MESH:C520809), valproic acid (MESH:D014635), lenalidomide (MESH:D000077269), HMA (-), imetelstat (MESH:C519562), azacitidine (MESH:D001374), glucose (MESH:D005947), ROS (MESH:D017382), lipid (MESH:D008055), cytarabine (MESH:D003561) - **Species:** Homo sapiens (human, species) [taxon 9606], Cosavirus F (no rank) [taxon 2003652] - **Cell lines:** MDS-L — Homo sapiens (Human), Myelodysplastic syndrome, Cancer cell line (CVCL_A647) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12913373/full.md ## Figures 2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12913373/full.md ## References 153 references — full list in the complete paper: https://tomesphere.com/paper/PMC12913373/full.md --- Source: https://tomesphere.com/paper/PMC12913373