CoChat
Sign Up
Cited by 28Acute Myeloid Leukemia ResearchCancer Genomics and DiagnosticsSingle-cell and spatial transcriptomics

Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia

Open access
Sirenko, Maria, Lee, Soobeom, Sun, Zhengxi, Chaligne, Ronan, Loghavi, Sanam, Asimomitis, Georgios, Brierley, Charlotte K., Bernard, Elsa +27 more·2025·Cell Stem Cell
DOI 10.1016/j.stem.2025.04.012PMC PMC12857296
Open this paper in CoChat — free account

Abstract

Isocitrate dehydrogenase 1/2 (IDH) mutations are early initiating events in acute myeloid leukemia (AML). The complex clonal architecture and cellular heterogeneity in IDH-mutant AML underlies the heterogeneous clinical presentation and outcomes. Integrating single-cell genotyping and transcriptomics, we demonstrate a stem-like and inflammatory phenotype of IDH-mutant AML and identify clone-specific programs associated with NPM1, NRAS, and SRSF2 co-mutations. Furthermore, these clones had distinct responses to treatment with combination IDH inhibitors and chemotherapy, including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. At relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated major histocompatibility complex (MHC) class II antigen presentation. At the pre-leukemic stage, we observe upregulation of IDH2-associated pathways, including inflammation. We deliver a detailed phenotyping of IDH-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and following therapy, with implications for precision medicine.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.stem.2025.04.012

Cites

12 of 12 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The rate of cell cycle entry of the mutated cells was already near or at the point of saturation due to the CALR mutation.

    “However, in contrast to the other myeloid progenitors, within the MkPs (wherein the CALR mutation exerts the greatest phenotypic effects due to the activation of the thrombopoietin receptor 21,54-57 ), the proliferative effects of IFNa were modest in the mutated cells compared to those at baseline ( Fig. 3e ), suggesting that the rate of cell cycle entry of the mutated cells was already near or at”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [54]

    The Results section on intratumoral transcriptional heterogeneity discusses cell-cycle activity in NRAS-mutant AML clones, not CALR-mutant megakaryocyte progenitors. Searches for CALR, IFNa, and saturation of cell-cycle entry found no passage in our copy addressing the claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Within the MkPs, the proliferative effects of IFNa were modest in the mutated cells compared to those at baseline.

    “However, in contrast to the other myeloid progenitors, within the MkPs (wherein the CALR mutation exerts the greatest phenotypic effects due to the activation of the thrombopoietin receptor 21,54-57 ), the proliferative effects of IFNa were modest in the mutated cells compared to those at baseline ( Fig. 3e ), suggesting that the rate of cell cycle entry of the mutated cells was already near or at”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [54]

    The Results sections on IDH-mutant AML discuss interferon-related gene expression at relapse and proliferation-associated pathways in particular clones, but not IFNα treatment of CALR-mutant MkPs. Searches for CALR, thrombopoietin-receptor activation, and modest proliferation relative to baseline found no passage addressing the claim. Page numbers were not supplied in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 83

  1. [1]Kantarjian H, Kadia T, DiNardo C, Daver N, Borthakur G, Jabbour E, Garcia-Manero G, Konopleva M, and Ravandi F (2021). Acute myeloid leukemia: current progress and future directions. Blood Cancer J. 11, 41. 10.1038/s41408-021-00425-3. 33619261 PMC7900255 · DOI
  2. [2]Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, Potter NE, Heuser M, Thol F, Bolli N, (2016). Genomic Classification and Prognosis in Acute Myeloid Leukemia. N. Engl. J. Med 374, 2209– 2221. 10.1056/NEJMoa1516192. 27276561 PMC4979995 · DOI · Paper page
  3. [3]Paschka P, Schlenk RF, Gaidzik VI, Habdank M, Krönke J, Bullinger L, Späth D, Kayser S, Zucknick M, Götze K, (2010). IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J. Clin. Oncol 28, 3636– 3643. 10.1200/JCO.2010.28.3762. 20567020 · DOI
  4. [4]Desai P, Mencia-Trinchant N, Savenkov O, Simon MS, Cheang G, Lee S, Samuel M, Ritchie EK, Guzman ML, Ballman KV, (2018). Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat. Med 24, 1015– 1023. 10.1038/s41591-018-0081-z. 29988143 PMC6849383 · DOI · Paper page
  5. [6]Young AL, Tong RS, Birmann BM, and Druley TE (2019). Clonal hematopoiesis and risk of acute myeloid leukemia. Haematologica 104, 2410– 2417. 10.3324/haematol.2018.215269. 31004019 PMC6959179 · DOI
  6. [7]Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, (2010). Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553– 567. 10.1016/j.ccr.2010.11.015. 21130701 PMC4105845 · DOI · Paper page
  7. [8]Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim S-H, Ito S, Yang C, Wang P, Xiao M-T, (2011). Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17– 30. 10.1016/j.ccr.2010.12.014. 21251613 PMC3229304 · DOI · Paper page
  8. [10]Kats LM, Reschke M, Taulli R, Pozdnyakova O, Burgess K, Bhargava P, Straley K, Karnik R, Meissner A, Small D, (2014). Proto-Oncogenic Role of Mutant IDH2 in Leukemia Initiation and Maintenance. Cell Stem Cell 14, 329– 341. 10.1016/j.stem.2013.12.016. 24440599 PMC4380188 · DOI
  9. [11]Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, Stone RM, DeAngelo DJ, Levine RL, Flinn IW, (2017). Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130, 722– 731. 10.1182/blood-2017-04-779405. 28588020 PMC5572791 · DOI · Paper page
  10. [12]DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA, (2018). Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N. Engl. J. Med 378, 2386– 2398. 10.1056/NEJMoa1716984. 29860938 · DOI
  11. [13]de Botton S, Brandwein JM, Wei AH, Pigneux A, Quesnel B, Thomas X, Legrand O, Recher C, Chantepie S, Hunault-Berger M, (2021). Improved survival with enasidenib versus standard of care in relapsed/refractory acute myeloid leukemia associated with IDH2 mutations using historical data and propensity score matching analysis. Cancer Med. 10, 6336– 6343. 10.1002/cam4.4182. 34427990 PMC8446562 · DOI
  12. [14]Pollyea DA, Tallman MS, de Botton S, Kantarjian HM, Collins R, Stein AS, Frattini MG, Xu Q, Tosolini A, See WL, (2019). Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia 33, 2575– 2584. 10.1038/s41375-019-0472-2. 30967620 PMC9724489 · DOI
  13. [15]Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, Altman JK, Arellano ML, Donnellan W, Erba HP, (2020). Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood 135, 463– 471. 10.1182/blood.2019002140. 31841594 PMC7019193 · DOI
  14. [16]Stein EM, DiNardo CD, Fathi AT, Mims AS, Pratz KW, Savona MR, Stein AS, Stone RM, Winer ES, Seet CS, (2021). Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study. Blood 137, 1792– 1803. 10.1182/blood.2020007233. 33024987 PMC8020270 · DOI
  15. [17]DiNardo CD, Schuh AC, Stein EM, Montesinos P, Wei AH, de Botton S, Zeidan AM, Fathi AT, Kantarjian HM, Bennett JM, (2021). Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 22, 1597– 1608. 10.1016/S1470-2045(21)00494-0. 34672961 · DOI
  16. [18]Montesinos P, Recher C, Vives S, Zarzycka E, Wang J, Bertani G, Heuser M, Calado RT, Schuh AC, Yeh S-P, (2022). Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N. Engl. J. Med 386, 1519– 1531. 10.1056/NEJMoa2117344. 35443108 · DOI
  17. [19]Amatangelo MD, Quek L, Shih A, Stein EM, Roshal M, David MD, Marteyn B, Farnoud NR, de Botton S, Bernard OA, (2017). Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 130, 732– 741. 10.1182/blood-2017-04-779447. 28588019 PMC5553578 · DOI
  18. [20]Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C, (2013). Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622– 626. 10.1126/science.1234769. 23558173 · DOI · Paper page
  19. [22]Choe S, Wang H, DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Watts JM, Pollyea DA, (2020). Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML. Blood Adv. 4, 1894– 1905. 10.1182/bloodadvances.2020001503. 32380538 PMC7218420 · DOI
  20. [23]van Galen P, Hovestadt V, Wadsworth MH, Hughes TK, Griffin GK, Battaglia S, Verga JA, Stephansky J, Pastika TJ, Lombardi Story J, (2019). Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity. Cell 176, 1265– 1281.e24. 10.1016/j.cell.2019.01.031. 30827681 PMC6515904 · DOI · Paper page
  21. [24]Lasry A, Nadorp B, Fornerod M, Nicolet D, Wu H, Walker CJ, Sun Z, Witkowski MT, Tikhonova AN, Guillamot-Ruano M, (2023). An inflammatory state remodels the immune microenvironment and improves risk stratification in acute myeloid leukemia. Nat. Cancer 4, 27– 42. 10.1038/s43018-022-00480-0. 36581735 PMC9986885 · DOI
  22. [26]Rodriguez-Meira A, Buck G, Clark S-A, Povinelli BJ, Alcolea V, Louka E, McGowan S, Hamblin A, Sousos N, Barkas N, (2019). Unravelling Intratumoral Heterogeneity through High-Sensitivity Single-Cell Mutational Analysis and Parallel RNA sequencing. Mol. Cell 73, 1292– 1305.e8. 10.1016/j.molcel.2019.01.009. 30765193 PMC6436961 · DOI · Paper page
  23. [27]Velten L, Story BA, Hernández-Malmierca P, Raffel S, Leonce DR, Milbank J, Paulsen M, Demir A, Szu-Tu C, Frömel R, (2021). Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics. Nat. Commun 12, 1366. 10.1038/s41467-021-21650-1. 33649320 PMC7921413 · DOI
  24. [30]Fan J, Lee H-O, Lee S, Ryu D-E, Lee S, Xue C, Kim SJ, Kim K, Barkas N, Park PJ, (2018). Linking transcriptional and genetic tumor heterogeneity through allele analysis of single-cell RNA-seq data. Genome Res. 28, 1217– 1227. 10.1101/gr.228080.117. 29898899 PMC6071640 · DOI
  25. [31]Gao T, Soldatov R, Sarkar H, Kurkiewicz A, Biederstedt E, Loh P-R, and Kharchenko PV (2023). Haplotype-aware analysis of somatic copy number variations from single-cell transcriptomes. Nat. Biotechnol 41, 417– 426. 10.1038/s41587-022-01468-y. 36163550 PMC10289836 · DOI
  26. [32]Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, (2009). Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med 361, 1058– 1066. 10.1056/NEJMoa0903840. 19657110 PMC3201812 · DOI · Paper page
  27. [33]Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson AG, Hoadley K, Triche TJ, Laird PW,; Cancer; Genome; Atlas; Research Network (2013). Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. N. Engl. J. Med 368, 2059– 2074. 10.1056/NEJMoa1301689. 23634996 PMC3767041 · DOI · Paper page
  28. [34]Tazi Y, Arango-Ossa JE, Zhou Y, Bernard E, Thomas I, Gilkes A, Freeman S, Pradat Y, Johnson SJ, Hills R, (2022). Unified classification and risk-stratification in acute myeloid leukemia. Nat. Commun 13, 4622. 10.1038/s41467-022-32103-8. 35941135 PMC9360033 · DOI
  29. [35]Miles LA, Bowman RL, Merlinsky TR, Csete IS, Ooi AT, Durruthy-Durruthy R, Bowman M, Famulare C, Patel MA, Mendez P, (2020). Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature 587, 477– 482. 10.1038/s41586-020-2864-x. 33116311 PMC7677169 · DOI
  30. [36]Bolton KL, Ptashkin RN, Gao T, Braunstein L, Devlin SM, Kelly D, Patel M, Berthon A, Syed A, Yabe M, (2020). Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat. Genet 52, 1219– 1226. 10.1038/s41588-020-00710-0. 33106634 PMC7891089 · DOI · Paper page
  31. [37]Zheng S, Papalexi E, Butler A, Stephenson W, and Satija R (2018). Molecular transitions in early progenitors during human cord blood hematopoiesis. Mol. Syst. Biol 14, e8041. 10.15252/msb.20178041. 29545397 PMC5852373 · DOI
  32. [38]Komorowska K, Doyle A, Wahlestedt M, Subramaniam A, Debnath S, Chen J, Soneji S, Van Handel B, Mikkola HKA, Miharada K, (2017). Hepatic Leukemia Factor Maintains Quiescence of Hematopoietic Stem Cells and Protects the Stem Cell Pool during Regeneration. Cell Rep. 21, 3514– 3523. 10.1016/j.celrep.2017.11.084. 29262330 · DOI
  33. [39]Karamitros D, Stoilova B, Aboukhalil Z, Hamey F, Reinisch A, Samitsch M, Quek L, Otto G, Repapi E, Doondeea J, (2018). Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells. Nat. Immunol 19, 85– 97. 10.1038/s41590-017-0001-2. 29167569 PMC5884424 · DOI
  34. [41]Velten L, Haas SF, Raffel S, Blaszkiewicz S, Islam S, Hennig BP, Hirche C, Lutz C, Buss EC, Nowak D, (2017). Human haematopoietic stem cell lineage commitment is a continuous process. Nat. Cell Biol 19, 271– 281. 10.1038/ncb3493. 28319093 PMC5496982 · DOI · Paper page
  35. [42]Popescu D-M, Botting RA, Stephenson E, Green K, Webb S, Jardine L, Calderbank EF, Polanski K, Goh I, Efremova M, (2019). Decoding human fetal liver haematopoiesis. Nature 574, 365– 371. 10.1038/s41586-019-1652-y. 31597962 PMC6861135 · DOI · Paper page
  36. [43]Lu Y-C, Sanada C, Xavier-Ferrucio J, Wang L, Zhang P-X, Grimes HL, Venkatasubramanian M, Chetal K, Aronow B, Salomonis N, (2018). The Molecular Signature of Megakaryocyte-Erythroid Progenitors Reveals a Role for the Cell Cycle in Fate Specification. Cell Rep. 25, 3229. 10.1016/j.celrep.2018.11.075. 30540953 PMC6357951 · DOI
  37. [44]Stoeckius M, Hafemeister C, Stephenson W, Houck-Loomis B, Chattopadhyay PK, Swerdlow H, Satija R, and Smibert P (2017). Simultaneous epitope and transcriptome measurement in single cells. Nat. Methods 14, 865– 868. 10.1038/nmeth.4380. 28759029 PMC5669064 · DOI · Paper page
  38. [45]Triana S, Vonficht D, Jopp-Saile L, Raffel S, Lutz R, Leonce D, Antes M, Hernández-Malmierca P, Ordoñez-Rueda D, Ramasz B, (2021). Single-cell proteo-genomic reference maps of the hematopoietic system enable the purification and massive profiling of precisely defined cell states. Nat. Immunol 22, 1577– 1589. 10.1038/s41590-021-01059-0. 34811546 PMC8642243 · DOI · Paper page
  39. [46]Zeng AGX, Bansal S, Jin L, Mitchell A, Chen WC, Abbas HA, Chan-Seng-Yue M, Voisin V, van Galen P, Tierens A, (2022). A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia. Nat. Med 28, 1212– 1223. 10.1038/s41591-022-01819-x. 35618837 · DOI
  40. [47]Beneyto-Calabuig S, Ludwig AK, Kniffka J-A, Szu-Tu C, Rohde C, Antes M, Waclawiczek A, Gräßle S, Pervan P, Janssen M, (2023). Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia. Cell Stem Cell 30, 706– 721. 10.1101/2022.08.29.505648. 37098346 · DOI
  41. [48]Zhang X, Wang X, Wang XQD, Su J, Putluri N, Zhou T, Qu Y, Jeong M, Guzman A, Rosas C, (2020). Dnmt3a loss and Idh2 neomorphic mutations mutually potentiate malignant hematopoiesis. Blood 135, 845– 856. 10.1182/blood.2019003330. 31932841 PMC7068035 · DOI
  42. [49]Kats LM, Vervoort SJ, Cole R, Rogers AJ, Gregory GP, Vidacs E, Li J, Nagaraja R, Yen KE, and Johnstone RW (2017). A pharmacogenomic approach validates AG-221 as an effective and on-target therapy in IDH2 mutant AML. Leukemia 31, 1466– 1470. 10.1038/leu.2017.84. 28280273 · DOI
  43. [50]Forte D, Salvestrini V, Corradi G, Rossi L, Catani L, Lemoli RM, Cavo M, and Curti A (2017). The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes survival and migration of acute myeloid leukemia cells through CD63/PI3K/Akt/p21 signaling. Oncotarget 8, 2261– 2274. 10.18632/oncotarget.13664. 27903985 PMC5356797 · DOI
  44. [51]Ball BJ, Hsu M, Devlin SM, Arcila M, Roshal M, Zhang Y, Famulare CA, Goldberg AD, Cai SF, Dunbar A, (2021). The prognosis and durable clearance of RAS mutations in patients with acute myeloid leukemia receiving induction chemotherapy. Am. J. Hematol 96, E171– E175. 10.1002/ajh.26146. 33650111 PMC8335797 · DOI
  45. [52]Avagyan S, Henninger JE, Mannherz WP, Mistry M, Yoon J, Yang S, Weber MC, Moore JL, and Zon LI (2021). Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis. Science 374, 768– 772. 10.1126/science.aba9304. 34735227 · DOI · Paper page
  46. [53]Wiseman DH, Williams EL, Wilks DP, Sun Leong H, Somerville TDD, Dennis MW, Struys EA, Bakkali A, Salomons GS, and Somervaille TCP (2016). Frequent reconstitution of IDH2R140Q mutant clonal multilineage hematopoiesis following chemotherapy for acute myeloid leukemia. Leukemia 30, 1946– 1950. 10.1038/leu.2016.93. 27118404 PMC5010144 · DOI
  47. [54]Abbas HA, Ayoub E, Sun H, Kanagal-Shamanna R, Short NJ, Issa G, Yilmaz M, Pierce S, Rivera D, Cham B, (2022). Clinical and molecular profiling of AML patients with chromosome 7 or 7q deletions in the context of TP53 alterations and venetoclax treatment. Leuk. Lymphoma 63, 3105– 3116. 10.1080/10428194.2022.2118533. 36089905 PMC9772202 · DOI
  48. [55]Gronseth CM, McElhone SE, Storer BE, Kroeger KA, Sandhu V, Fero ML, Appelbaum FR, Estey EH, and Fang M (2015). Prognostic significance of acquired copy-neutral loss of heterozygosity in acute myeloid leukemia. Cancer 121, 2900– 2908. 10.1002/cncr.29475. 26033747 · DOI
  49. [56]Walker CJ, Kohlschmidt J, Eisfeld A-K, Mrózek K, Liyanarachchi S, Song C, Nicolet D, Blachly JS, Bill M, Papaioannou D, (2019). Genetic characterization and prognostic relevance of acquired uniparental disomies in cytogenetically normal acute myeloid leukemia. Clin. Cancer Res 25, 6524– 6531. 10.1158/1078-0432.CCR-19-0725. 31375516 PMC6825549 · DOI
  50. [57]Ayoub E, Wilson MP, McGrath KE, Li AJ, Frisch BJ, Palis J, Calvi LM, Zhang Y, and Perkins AS (2018). EVI1 overexpression reprograms hematopoiesis via upregulation of Spi1 transcription. Nat. Commun 9, 4239. 10.1038/s41467-018-06208-y. 30315161 PMC6185954 · DOI
  51. [58]Ng SWK, Mitchell A, Kennedy JA, Chen WC, McLeod J, Ibrahimova N, Arruda A, Popescu A, Gupta V, Schimmer AD, (2016). A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature 540, 433– 437. 10.1038/nature20598. 27926740 · DOI · Paper page
  52. [60]Lasorella A, Benezra R, and Iavarone A (2014). The ID proteins: master regulators of cancer stem cells and tumour aggressiveness. Nat. Rev. Cancer 14, 77– 91. 10.1038/nrc3638. 24442143 · DOI
  53. [61]Coombs CC, Zehir A, Devlin SM, Kishtagari A, Syed A, Jonsson P, Hyman DM, Solit DB, Robson ME, Baselga J, (2017). Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes. Cell Stem Cell. 21, 374– 382.e4. 10.1016/j.stem.2017.07.010. 28803919 PMC5591073 · DOI · Paper page
  54. [62]Chen C, Liu Y, Lu C, Cross JR, Morris JP 4th, Shroff AS, Ward PS, Bradner JE, Thompson C, and Lowe SW (2013). Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes Dev. 27, 1974– 1985. 10.1101/gad.226613.113. 24065765 PMC3792474 · DOI
  55. [63]Mylonas E, Janin M, Bawa O, Opolon P, David M, Quivoron C, Bernard OA, Ottolenghi C, DeBotton S, and Penard-Lacronique V (2014). Isocitrate dehydrogenase (IDH)2 R140Q mutation induces myeloid and lymphoid neoplasms in mice. Leukemia 28, 1343– 1346. 10.1038/leu.2014.18. 24418992 · DOI
  56. [64]Yeaton A, Cayanan G, Loghavi S, Dolgalev I, Leddin EM, Loo CE, Torabifard H, Nicolet D, Wang J, Corrigan K, (2022). The Impact of Inflammation-Induced Tumor Plasticity during Myeloid Transformation. Cancer Discov. 12, 2392– 2413. 10.1158/2159-8290.CD-21-1146. 35924979 PMC9547930 · DOI
  57. [65]Gruber E, So J, Lewis AC, Franich R, Cole R, Martelotto LG, Rogers AJ, Vidacs E, Fraser P, Stanley K, (2022). Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells. Cell Rep. 40, 111182. 10.1016/j.celrep.2022.111182. 35977494 · DOI
  58. [67]Bralten LBC, Kloosterhof NK, Balvers R, Sacchetti A, Lapre L, Lamfers M, Leenstra S, de Jonge H, Kros JM, Jansen EEW, (2011). IDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo. Ann. Neurol 69, 455– 463. 10.1002/ana.22390. 21446021 · DOI
  59. [69]Fu X, Chin RM, Vergnes L, Hwang H, Deng G, Xing Y, Pai MY, Li S, Ta L, Fazlollahi F, (2015). 2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling. Cell Metab. 22, 508– 515. 10.1016/j.cmet.2015.06.009. 26190651 PMC4663076 · DOI
  60. [71]Zeng P, Lu W, Tian J, Qiao S, Li J, Glorieux C, Wen S, Zhang H, Li Y, and Huang P (2022). Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy. J. Hematol. Oncol 15, 30. 10.1186/s13045-022-01245-z. 35313945 PMC8935709 · DOI
  61. [72]Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, Liu Y, Sundaram RK, Hegan DC, Fons NR, (2017). 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci. Transl. Med 9, eaal2463. 10.1126/sci-translmed.aal2463. 28148839 PMC5435119 · DOI
  62. [73]Gbyli R, Song Y, Liu W, Gao Y, Chandhok NS, Fu X, Wang X, Patel A, Sundaram R, Tebaldi T, (2019). PARP Inhibitors Are Effective in IDH1/2 Mutant MDS and AML Resistant to Targeted IDH Inhibitors. Blood 134, 4222. 10.1182/blood-2019-130814. · DOI
  63. [74]Gbyli R, Song Y, Liu W, Gao Y, Biancon G, Chandhok NS, Wang X, Fu X, Patel A, Sundaram R, (2022). In vivo anti-tumor effect of PARP inhibition in IDH1/2 mutant MDS/AML resistant to targeted inhibitors of mutant IDH1/2. Leukemia 36, 1313– 1323. 10.1038/s41375-022-01536-x. 35273342 PMC9103411 · DOI
  64. [75]Schvartzman J-M, Forsyth G, Walch H, Chatila W, Taglialatela A, Lee BJ, Zhu X, Gershik S, Cimino FV, Santella A, (2023). Oncogenic IDH mutations increase heterochromatin-related replication stress without impacting homologous recombination. Mol. Cell 83, 2347– 2356.e8. 10.1016/j.molcel.2023.05.026. 37311462 PMC10845120 · DOI
  65. [76]Sango J, Carcamo S, Sirenko M, Maiti A, Mansour H, Ulukaya G, Tomalin LE, Cruz-Rodriguez N, Wang T, Olszewska M, (2024). RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax. Nature 636, 241– 250. 10.1038/s41586-024-08137-x. 39478230 PMC11618090 · DOI
  66. [77]Fiskus W, Boettcher S, Daver N, Mill CP, Sasaki K, Birdwell CE, Davis JA, Takahashi K, Kadia TM, DiNardo CD, (2022). Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c). Blood Cancer J. 12, 5. 10.1038/s41408-021-00603-3. 35017466 PMC8752621 · DOI
  67. [78]Yoon JJ, Miao H, Purohit T, Chen D, Cierpicki T, and Grembecka J (2022). Combination of Menin and IDH Mutant Inhibition in Acute Myeloid Leukemia. Blood 140, 5946. 10.1182/blood-2022-168834. · DOI
  68. [79]Wang F, Morita K, DiNardo CD, Furudate K, Tanaka T, Yan Y, Patel KP, MacBeth KJ, Wu B, Liu G, (2021). Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia. Nat. Commun 12, 2607. 10.1038/s41467-021-22874-x. 33972549 PMC8110775 · DOI
  69. [80]Stuani L, Sabatier M, Saland E, Cognet G, Poupin N, Bosc C, Castelli FA, Gales L, Turtoi E, Montersino C, (2021). Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia. J. Exp. Med 218, e20200924. 10.1084/jem.20200924. 33760042 PMC7995203 · DOI
  70. [81]Christopher MJ, Petti AA, Rettig MP, Miller CA, Chendamarai E, Duncavage EJ, Klco JM, Helton NM, O’Laughlin M, Fronick CC, (2018). Immune Escape of Relapsed AML Cells after Allogeneic Transplantation. N. Engl. J. Med 379, 2330– 2341. 10.1056/NEJMoa1808777. 30380364 PMC6322675 · DOI
  71. [82]Toffalori C, Zito L, Gambacorta V, Riba M, Oliveira G, Bucci G, Barcella M, Spinelli O, Greco R, Crucitti L, (2019). Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation. Nat. Med 25, 603– 611. 10.1038/s41591-019-0400-z. 30911134 · DOI
  72. [83]Shahid S, Ceglia N, Le Luduec J-B, McPherson A, Spitzer B, Bojilova V, Panjwani MK, Roshal M, Shah S, Abdel-Wahab O, (2022). Immune Escape after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients with Acute Myeloid Leukemia. Blood 140, 10209– 10210. 10.1182/blood-2022-162436. PMC10471937 37327118 · DOI
  73. [84]Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A, (2014). Agerelated clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med 371, 2488– 2498. 10.1056/NEJMoa1408617. 25426837 PMC4306669 · DOI · Paper page
  74. [85]Weeks LD, Niroula A, Neuberg D, Wong W, Lindsley RC, Luskin M, Berliner N, Stone RM, DeAngelo DJ, Soiffer R, (2023). Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis. NEJM Evid. 2, EVIDoa2200310. 10.1056/EVIDoa2200310. PMC10361696 37483562 · DOI
  75. [89]Bernard E, Nannya Y, Hasserjian RP, Devlin SM, Tuechler H, Medina-Martinez JS, Yoshizato T, Shiozawa Y, Saiki R, Malcovati L, (2021). Author Correction: Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat. Med 27, 927. 10.1038/s41591-021-01367-w. 33948021 · DOI
  76. [90]Medina-Martníez JS, Arango-Ossa JE, Levine MF, Zhou Y, Gundem G, Kung AL, and Papaemmanuil E (2020). Isabl Platform, a digital biobank for processing multimodal patient data. BMC Bioinformatics 21, 549. 10.1186/s12859-020-03879-7. 33256603 PMC7708092 · DOI
  77. [91]Hao Y, Hao S, Andersen-Nissen E, Mauck WM 3rd, Zheng S, Butler A, Lee MJ, Wilk AJ, Darby C, Zager M, (2021). Integrated analysis of multimodal single-cell data. Cell 184, 3573– 3587.e29. 10.1016/j.cell.2021.04.048. 34062119 PMC8238499 · DOI · Paper page
  78. [92]Butler A, Hoffman P, Smibert P, Papalexi E, and Satija R (2018). Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol 36, 411– 420. 10.1038/nbt.4096. 29608179 PMC6700744 · DOI · Paper page
  79. [93]Psaila B, Barkas N, Iskander D, Roy A, Anderson S, Ashley N, Caputo VS, Lichtenberg J, Loaiza S, Bodine DM, (2016). Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways. Genome Biol. 17, 83. 10.1186/s13059-016-0939-7. 27142433 PMC4855892 · DOI
  80. [94]Aibar S, González-Blas CB, Moerman T, Huynh-Thu VA, Imrichova H, Hulselmans G, Rambow F, Marine J-C, Geurts P, Aerts J, (2017). SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083– 1086. 10.1038/nmeth.4463. 28991892 PMC5937676 · DOI · Paper page
  81. [96]Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, and Tamayo P (2015). The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 1, 417– 425. 10.1016/j.cels.2015.12.004. 26771021 PMC4707969 · DOI · Paper page
  82. [97]Tirosh I, Venteicher AS, Hebert C, Escalante LE, Patel AP, Yizhak K, Fisher JM, Rodman C, Mount C, Filbin MG, (2016). Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature 539, 309– 313. 10.1038/nature20123. 27806376 PMC5465819 · DOI
  83. [98]Tirosh I, Izar B, Prakadan SM, Wadsworth MH 2nd, Treacy D, Trombetta JJ, Rotem A, Rodman C, Lian C, Murphy G, (2016). Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189– 196. 10.1126/science.aad0501. 27124452 PMC4944528 · DOI · Paper page

Cited by

Sorted by citations

Authors
Sirenko, M., Lee, S., Sun, Z., Chaligne, R., Loghavi, S., Asimomitis, G., Brierley, C. K., Bernard, E., Cai, S. F., Myers, R. M., Nadorp, B., Sango, J., Lallo, M., Levine, M. F., Domenico, D., Arango Ossa, J. E., Medina-Martinez, J. S., Menghrajani, K., Lasry, A., Mims, A. S., Desai, H., Laganson, A., Famulare, C., Patel, M., Lozanski, G., Bolton, K. L., Viny, A. D., Roshal, M., Levine, R. L., Papapetrou, E. P., Stein, E. M., Landau, D. A., Eisfeld, A.-K., Aifantis, I., & Papaemmanuil, E.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • New York University (US)
  • NYU Langone’s Laura and Isaac Perlmutter Cancer Center (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • University of Oxford (GB)
  • NYU Langone Health (US)
  • Tisch Cancer Institute (US)
  • The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
  • Washington University in St. Louis (US)
  • Columbia University Irving Medical Center (US)
  • New York Genome Center (US)
Corresponding author
Papaemmanuil, Elli
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2025-07
Volume
32
Issue
7
Pages
1102-1121.e5
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2025.04.012
PMC
PMC12857296
OpenAlex
W4410597204
Cited by
28
References
12
Citations by year
2026: 21 · 2025: 7
FWCI
20.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • Mark Foundation For Cancer Research
  • National Heart, Lung, and Blood Institute (R01HL157387, R01CA262496, R01CA284595, R01HL128239, R01CA283574, R01 LM013879)
  • American Cancer Society
  • Leukemia Research Foundation
  • Burroughs Wellcome Fund
  • Leukemia and Lymphoma Society
  • National Cancer Institute (F31-CA254130)
  • Damon Runyon Cancer Research Foundation
  • Cancer Research Institute (CRI5751)
  • New York State Stem Cell Science (C322560GG, R01CA271418, K08CA241371, C32558GG, R01CA260711, R01CA271331)
  • National Institutes of Health
  • Henry and Marilyn Taub Foundation (P50 CA254838-01, 1RO1CA271455, 5RO1CA228135, 1RO1HL159175, 5RO1CA242020)
  • National Institute of General Medical Sciences (T32GM007739)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
clonal architecture, cellular heterogeneity, IDH inhibitors, inflammation, mitochondrial metabolism, MHC class II antigen presentation, relapse, single-cell genotyping, transcriptomics, chemotherapy response, precision medicine
MeSH terms
Nucleophosmin, Animals, Clone Cells, Humans, Isocitrate Dehydrogenase, Mutation, Leukemia, Myeloid, Acute

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review