1,762
Views
1
CrossRef citations to date
0
Altmetric
Review Articles

Precision and strategic targeting of novel mutation-specific vulnerabilities in acute myeloid leukemia: the semi-centennial of 7 + 3

ORCID Icon
Pages 1503-1513 | Received 03 May 2023, Accepted 05 Jun 2023, Published online: 16 Jun 2023

References

  • Tyner JW, Tognon CE, Bottomly D, et al. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018;562(7728):526–531. doi: 10.1038/s41586-018-0623-z.
  • Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–2221. doi: 10.1056/NEJMoa1516192.
  • Ley TJ, Mardis ER, Ding L, et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008;456(7218):66–72. doi: 10.1038/nature07485.
  • Ley TJ, Miller C, Ding L, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–2074.
  • Lowenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361(13):1235–1248. doi: 10.1056/NEJMoa0901409.
  • Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454–464. doi: 10.1056/NEJMoa1614359.
  • Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-Mutated AML. N Engl J Med. 2019;381(18):1728–1740. doi: 10.1056/NEJMoa1902688.
  • Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722–731. doi: 10.1182/blood-2017-04-779405.
  • DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-Mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386–2398. doi: 10.1056/NEJMoa1716984.
  • Watts JM, Baer MR, Yang J, et al. Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial. Lancet Haematol. 2023;10(1):e46–e58. doi: 10.1016/S2352-3026(22)00292-7.
  • Patel SA, Gerber JM. A user’s guide to novel therapies for acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2020;20(5):277–288. doi: 10.1016/j.clml.2020.01.011.
  • Sinha S, Thomas D, Chan S, et al. Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data. Nat Commun. 2017;8:15580. doi: 10.1038/ncomms15580.
  • Chan SM, Thomas D, Corces-Zimmerman MR, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21(2):178–184. doi: 10.1038/nm.3788.
  • Petroni G, Buqué A, Coussens LM, et al. Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment. Nat Rev Drug Discov. 2022;21(6):440–462. doi: 10.1038/s41573-022-00415-5.
  • Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645–648. doi: 10.1038/367645a0.
  • Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730–737. doi: 10.1038/nm0797-730.
  • Patel SA, Lloyd MR, Cerny J, et al. Clinico-genomic profiling and clonal dynamic modeling of TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia. Leuk Lymphoma. 2021;62(14):3348–3360. doi: 10.1080/10428194.2021.1957869.
  • Mazumdar C, Shen Y, Xavy S, et al. Leukemia-Associated cohesin mutants dominantly enforce stem cell programs and impair human hematopoietic progenitor differentiation. Cell Stem Cell. 2015;17(6):675–688. doi: 10.1016/j.stem.2015.09.017.
  • Viny AD, Bowman RL, Liu Y, et al. Cohesin members Stag1 and Stag2 display distinct roles in chromatin accessibility and topological control of HSC Self-Renewal and differentiation. Cell Stem Cell. 2019;25(5):682–696.e8. doi: 10.1016/j.stem.2019.08.003.
  • van der Lelij P, Lieb S, Jude J, et al. Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts. Elife. 2017;6:e26980. doi: 10.7554/eLife.26980.
  • Tothova Z, Valton AL, Gorelov RA, et al. Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML. JCI Insight. 2021;6(3):e142149. doi: 10.1172/jci.insight.142149.
  • Sweet K, Bhatnagar B, Döhner H, et al. A 2:1 randomized, open-label, phase II study of selinexor vs. physician’s choice in older patients with relapsed or refractory acute myeloid leukemia. Leuk Lymphoma. 2021;62(13):3192–3203. doi: 10.1080/10428194.2021.1950706.
  • Heimbruch KE, Fisher JB, Stelloh CT, et al. DOT1L inhibitors block abnormal self-renewal induced by cohesin loss. Sci Rep. 2021;11(1):7288. doi: 10.1038/s41598-021-86646-9.
  • Wang E, Lu SX, Pastore A, et al. Targeting an RNA-Binding protein network in acute myeloid leukemia. Cancer Cell. 2019;35(3):369–384.e7. doi: 10.1016/j.ccell.2019.01.010.
  • Finci LI, Zhang X, Huang X, et al. The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action. Genes Dev. 2018;32(3-4):309–320. doi: 10.1101/gad.311043.117.
  • Seiler M, Yoshimi A, Darman R, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med. 2018;24(4):497–504. doi: 10.1038/nm.4493.
  • Steensma DP, Wermke M, Klimek VM, et al. Phase I first-in-Human dose escalation study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms. Leukemia. 2021;35(12):3542–3550. doi: 10.1038/s41375-021-01328-9.
  • Mian SA, Philippe C, Maniati E, et al. Vitamin B5 and succinyl-CoA improve ineffective erythropoiesis in SF3B1-mutated myelodysplasia. Sci Transl Med. 2023;15(685):eabn5135. doi: 10.1126/scitranslmed.abn5135.
  • Brunetti L, Gundry MC, Sorcini D, et al. Mutant NPM1 maintains the leukemic state through HOX expression. Cancer Cell. 2018;34(3):499–512.e9. doi: 10.1016/j.ccell.2018.08.005.
  • Kuhn MW, Song E, Feng Z, et al. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 2016;6(10):1166–1181. doi: 10.1158/2159-8290.CD-16-0237.
  • Gionfriddo I, Brunetti L, Mezzasoma F, et al. Dactinomycin induces complete remission associated with nucleolar stress response in relapsed/refractory NPM1-mutated AML. Leukemia. 2021;35(9):2552–2562. doi: 10.1038/s41375-021-01192-7.
  • Pianigiani G, Gagliardi A, Mezzasoma F, et al. Prolonged XPO1 inhibition is essential for optimal antileukemic activity in NPM1-mutated AML. Blood Adv. 2022;6(22):5938–5949. doi: 10.1182/bloodadvances.2022007563.
  • Chua CC, Reynolds J, Salmon JM, et al. Anti-Leukemic activity of single agent venetoclax in newly diagnosed acute myeloid leukemia: a Sub-Set analysis of the caveat study. Blood. 2019;134(Supplement_1):462–462. doi: 10.1182/blood-2019-126640.
  • Bernard E, Nannya Y, Hasserjian RP, et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat Med. 2020;26(10):1549–1556. doi: 10.1038/s41591-020-1008-z.
  • Bernard E, Tuechler H, Greenberg PL, et al. Molecular international prognostic scoring system for myelodysplastic syndromes. NEJM Evid. 2022;1:1–14.
  • Patel SA, Cerny J. TP53-mutant myelodysplastic syndrome and acute myeloid leukemia: the black hole of hematology. Blood Adv. 2022;6(6):1917–1918. doi: 10.1182/bloodadvances.2021006580.
  • Welch JS, Petti AA, Miller CA, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016;375(21):2023–2036. doi: 10.1056/NEJMoa1605949.
  • Sallman DA, DeZern AE, Garcia-Manero G, et al. Eprenetapopt (APR-246) and azacitidine in TP53-Mutant myelodysplastic syndromes. J Clin Oncol. 2021;39(14):1584–1594. doi: 10.1200/JCO.20.02341.
  • Cluzeau T, Sebert M, Rahmé R, et al. Eprenetapopt plus azacitidine in TP53-Mutated myelodysplastic syndromes and acute myeloid leukemia: a phase II study by the groupe francophone des myélodysplasies (GFM). J Clin Oncol. 2021;39(14):1575–1583. doi: 10.1200/JCO.20.02342.
  • Mishra A, Tamari R, DeZern AE, et al. Eprenetapopt plus azacitidine after allogeneic hematopoietic Stem-Cell transplantation for TP53-Mutant acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol. 2022;40(34):3985–3993. doi: 10.1200/JCO.22.00181.
  • Majeti R, Chao MP, Alizadeh AA, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138(2):286–299. doi: 10.1016/j.cell.2009.05.045.
  • Jaiswal S, Jamieson CH, Pang WW, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 2009;138(2):271–285. doi: 10.1016/j.cell.2009.05.046.
  • Sallman DA, Asch AS, Al Malki MM, et al. The first-in-Class anti-CD47 antibody magrolimab (5F9) in combination with azacitidine is effective in MDS and AML patients: ongoing phase 1b results. Blood. 2019;134(Supplement_1):569–569. doi: 10.1182/blood-2019-126271.
  • Sallman DA, Al Malki MM, Asch AS, et al. Magrolimab in combination with azacitidine in patients with Higher-Risk myelodysplastic syndromes: final results of a phase Ib study. J Clin Oncol. 2023;41(15):2815–2826.
  • Kojima K, Konopleva M, Samudio IJ, et al. MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy. Blood. 2005;106(9):3150–3159. doi: 10.1182/blood-2005-02-0553.
  • Andreeff M, Kelly KR, Yee K, et al. Results of the phase I trial of RG7112, a Small-Molecule MDM2 antagonist in leukemia. Clin Cancer Res. 2016;22(4):868–876. doi: 10.1158/1078-0432.CCR-15-0481.
  • Konopleva MY, Röllig C, Cavenagh J, et al. Idasanutlin plus cytarabine in relapsed or refractory acute myeloid leukemia: results of the MIRROS trial. Blood Adv. 2022;6(14):4147–4156. doi: 10.1182/bloodadvances.2021006303.
  • Daver NG, Dail M, Garcia JS, et al. Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial. Blood. 2023;141(11):1265–1276. doi: 10.1182/blood.2022016362.
  • Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058–1066. doi: 10.1056/NEJMoa0903840.
  • Thomas D, Wu M, Nakauchi Y, et al. Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability. Cancer Discov. 2023;13(2):496–515. doi: 10.1158/2159-8290.CD-21-0218.
  • Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-Mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519–1531. doi: 10.1056/NEJMoa2117344.
  • de Botton S, Fenaux P, Yee KWL, et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. Blood Adv. 2023;
  • Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol. 2010;28(14):2348–2355. doi: 10.1200/JCO.2009.27.3730.
  • de Botton S, Montesinos P, Schuh AC, et al. Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial. Blood. 2023;141(2):156–167. doi: 10.1182/blood.2021014901.
  • Rollig C, Serve H, Hüttmann A, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015;16(16):1691–1699. doi: 10.1016/S1470-2045(15)00362-9.
  • Levis MJ, Hamadani M, Logan BR, et al. BMT CTN protocol 1506: a phase 3 trial of gilteritinib as maintenance therapy after allogeneic hematopoietic stem cell transplantation in patients with FLT3-ITD + AML. Blood. 2019;134(Supplement_1):4602–4602. doi: 10.1182/blood-2019-124322.
  • Cortes JE, Khaled S, Martinelli G, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019;20(7):984–997. doi: 10.1016/S1470-2045(19)30150-0.
  • Brauchle B, Goldstein RL, Karbowski CM, et al. Characterization of a novel FLT3 BiTE molecule for the treatment of acute myeloid leukemia. Mol Cancer Ther. 2020;19(9):1875–1888. doi: 10.1158/1535-7163.MCT-19-1093.
  • McKeown MR, Corces MR, Eaton ML, et al. Superenhancer analysis defines novel epigenomic subtypes of Non-APL AML, including an RARα dependency targetable by SY-1425, a potent and selective RARα agonist. Cancer Discov. 2017;7(10):1136–1153. doi: 10.1158/2159-8290.CD-17-0399.
  • Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111–121. doi: 10.1056/NEJMoa1300874.
  • Bill M, Mrózek K, Kohlschmidt J, et al. Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/KMT2A. Proc Natl Acad Sci U S A. 2020;117(42):26340–26346. doi: 10.1073/pnas.2014732117.
  • Daigle SR, Olhava EJ, Therkelsen CA, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013;122(6):1017–1025. doi: 10.1182/blood-2013-04-497644.
  • Krivtsov AV, Evans K, Gadrey JY, et al. A Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-Rearranged leukemia. Cancer Cell. 2019;36(6):660–673.e11. doi: 10.1016/j.ccell.2019.11.001.
  • Stein EM, Aldoss I, DiPersio JF, et al. Safety and efficacy of menin inhibition in patients (pts) with MLL-Rearranged and NPM1 mutant acute leukemia: a phase (Ph) 1, first-in-Human study of SNDX-5613 (AUGMENT 101). Blood. 2021;138(Supplement 1):699–699. doi: 10.1182/blood-2021-146944.
  • Wang ES, Montesinos P, Minden MD, et al. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut + AML ineligible for intensive chemotherapy. Blood. 2022;140(17):1845–1857. doi: 10.1182/blood.2021014586.