Fol. Biol. 2026, 72, 1-15
https://doi.org/10.14712/fb2026.0002
Targeting FLT-3 Mutations in Acute Myeloid Leukaemia: from Molecular Insights to Clinical Strategies
Mohammadreza Afshari
, Martina Řezáčová, Darina Muthná
, Martina Řezáčová, Darina Muthná
Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic
Received August 20, 2025
Accepted December 17, 2025
References
1. , R., Amador, C., Anagnostopoulos, I. et al. (2022) The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia 36, 1720-1748.
<https://doi.org/10.1038/s41375-022-01620-2>
2. , D. R., Cohen, P. (1998) Mechanism of activation and function of protein kinase B. Curr. Opin. Genet. Dev. 8, 55-62.
<https://doi.org/10.1016/S0959-437X(98)80062-2>
3. , S., Su, M., Jones, J. W. et al. (2015) Human bone marrow niche chemoprotection mediated by cytochrome P450 enzymes. Oncotarget 6, 14905-14912.
<https://doi.org/10.18632/oncotarget.3614>
4. , A. S., Yilmaz, M., Kanagal-Shamanna, R. et al. (2021) Patterns of resistance differ in patients with acute myeloid leukemia treated with type I versus type II FLT3 inhibitors. Blood Cancer Discov. 2, 125-134.
<https://doi.org/10.1158/2643-3230.BCD-20-0143>
5. , D. A., Orazi, A., Hasserjian, R. P. et al. (2022) International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood 140, 1200-1228.
<https://doi.org/10.1182/blood.2022015850>
6. , A., Guerreiro, A. S. (2007) The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications. Curr. Genomics 8, 271-306.
<https://doi.org/10.2174/138920207782446160>
7. Cancer Genome Atlas Research Network, , T. J., Miller, C. et al. (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059-2074.
8. , U., Wang, M., Hu, J. (2020) Targeting aberrant RAS/RAF/MEK/ERK signaling for cancer therapy. Cells 9, 198.
<https://doi.org/10.3390/cells9010198>
9. , R. H., Zandvakili, N., Bohlander, S. K. (2022) Dissecting the genetic and non-genetic heterogeneity of acute myeloid leukemia using next-generation sequencing and in vivo models. Cancers (Basel) 14, 2182.
<https://doi.org/10.3390/cancers14092182>
10. , S. P., Daver, N., DiNardo, C. et al. (2022) Resistance to targeted therapies: delving into FLT3 and IDH. Blood Cancer J. 12, 91.
<https://doi.org/10.1038/s41408-022-00687-5>
11. , H., Wei, A. H., Appelbaum, F. R. et al. (2022) Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140, 1345-1377.
<https://doi.org/10.1182/blood.2022016867>
12. , H., Wei, A. H., Appelbaum, F. R. et al. (2022) Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140, 1345-1377.
<https://doi.org/10.1182/blood.2022016867>
13. , H., Weisdorf, D. J., Bloomfield, C. D. (2015) Acute myeloid leukemia. N. Engl. J. Med. 373, 1136-1152.
<https://doi.org/10.1056/NEJMra1406184>
14. , H. G., Quentmeier, H. (2004) FLT3: receptor and ligand. Growth Factors 22, 71-73.
<https://doi.org/10.1080/08977190410001700989>
15. , M., Minami, Y., Kuzume, A. et al. (2020) Mechanisms underlying resistance to FLT3 inhibitors in acute myeloid leukemia. Biomedicines 8, 245.
<https://doi.org/10.3390/biomedicines8080245>
16. , H. P., Montesinos, P., Kim, H. J. et al. (2023) Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 401, 1571-1583.
<https://doi.org/10.1016/S0140-6736(23)00464-6>
17. , B., Martelli, M. P. (2023) Comparison of the international consensus and 5th WHO edition classifications of adult myelodysplastic syndromes and acute myeloid leukemia. Am. J. Hematol. 98, 481-492.
<https://doi.org/10.1002/ajh.26812>
18. , D. A., Chiu, H., Hopkins, B. D. et al. (2017) The PI3K pathway in human disease. Cell 170, 605-635.
<https://doi.org/10.1016/j.cell.2017.07.029>
19. , E., Jimeno, A. (2014) Nivolumab. Drugs Today (Barc.) 50, 791-802.
<https://doi.org/10.1358/dot.2014.50.12.2235103>
20. , S. S., Liu, S. B., Xue, S. L. (2022) Developments and challenges of FLT3 inhibitors in acute myeloid leukemia. Front. Oncol. 12, 996438.
<https://doi.org/10.3389/fonc.2022.996438>
21. , D. G., Griffin, J. D. (2002) The roles of FLT3 in hematopoiesis and leukemia. Blood 100, 1532-1542.
<https://doi.org/10.1182/blood-2002-02-0492>
22. , T., Palmisano, M., Nicci, C. et al. (2012) An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment. Oncol. Rev. 6, e8.
<https://doi.org/10.4081/oncol.2012.e8>
23. , Å., Kontro, M., Haller, K. et al. (2023) Personalizing precision medicine: patients with AML perceptions about treatment decisions. Patient Educ. Couns. 115, 107883.
<https://doi.org/10.1016/j.pec.2023.107883>
24. , J., Black, J., Faerman, C. et al. (2004) The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol. Cell 13, 169-178.
<https://doi.org/10.1016/S1097-2765(03)00505-7>
25. , C. S., Vassiliou, G. S. (2014) Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer? Dis. Models Mech. 7, 941-951.
<https://doi.org/10.1242/dmm.015974>
26. , A., Richer, C., Ouimet, M. et al. (2024) Characterisation of FLT3 alterations in childhood acute lymphoblastic leukaemia. Br. J. Cancer 130, 317-326.
<https://doi.org/10.1038/s41416-023-02511-8>
27. , S. K., Hunter, T. (1995) The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9, 576-596.
<https://doi.org/10.1096/fasebj.9.8.7768349>
28. , D. A. (2012) The Jak/STAT pathway. Cold Spring Harbor Perspect. Biol. 4, a011205.
<https://doi.org/10.1101/cshperspect.a011205>
29. , H. M., Dokla, E. M. E., Elrazaz, E. Z. et al. (2024) FLT3-PROTACs for combating AML resistance: analytical overview on chimeric agents developed, challenges, and future perspectives. Eur. J. Med. Chem. 277, 116717.
<https://doi.org/10.1016/j.ejmech.2024.116717>
30. , M., Freeman, S. D., Ossenkoppele, G. J. et al. (2021) 2021 update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood 138, 2753-2767.
<https://doi.org/10.1182/blood.2021013626>
31. , M., Kuriyan, J. (2002) The conformational plasticity of protein kinases. Cell 109, 275-282.
<https://doi.org/10.1016/S0092-8674(02)00741-9>
32. , S., Levis, M. J. (2022) Updates on targeted therapies for acute myeloid leukaemia. Br. J. Haematol. 196, 316-328.
<https://doi.org/10.1111/bjh.17746>
33. , J. U., Rönnstrand, L. (2019a) FMS-like tyrosine kinase 3/FLT3: from basic science to clinical implications. Physiol. Rev. 99, 1433-1466.
<https://doi.org/10.1152/physrev.00029.2018>
34. , J. U., Rönnstrand, L. (2019b) The role of SRC family kinases in FLT3 signaling. Int. J. Biochem. Cell Biol. 107, 32-37.
<https://doi.org/10.1016/j.biocel.2018.12.007>
35. , V. E., Smith, C. C. (2020) FLT3 mutations in acute myeloid leukemia: key concepts and emerging controversies. Front. Oncol. 10, 612880.
<https://doi.org/10.3389/fonc.2020.612880>
36. , J. D., Solary, E., Abla, O. et al. (2022) The 5th edition of the World Health Organization Classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia 36, 1703-1719.
<https://doi.org/10.1038/s41375-022-01613-1>
37. , Y., Yoshimoto, G., Miyamoto, T. et al. (2008) Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival. J. Immunol. 180, 7358-7367.
<https://doi.org/10.4049/jimmunol.180.11.7358>
38. , H., Kawashima, N., Ishikawa, Y. (2020) FLT3 mutations in acute myeloid leukemia: therapeutic paradigm beyond inhibitor development. Cancer Sci. 111, 312-322.
<https://doi.org/10.1111/cas.14274>
39. , G., Yau, T. C., Chiu, J. W. et al. (2016) Pembrolizumab (Keytruda). Hum. Vaccin. Immunother. 12, 2777-2789.
<https://doi.org/10.1080/21645515.2016.1199310>
40. , C. A., Long, N., Saultz, J. et al. (2023) Comparison and validation of the 2022 European LeukemiaNet guidelines in acute myeloid leukemia. Blood Adv. 7, 1899-1909.
<https://doi.org/10.1182/bloodadvances.2022009010>
41. , M., Baer, M. R. (2017) FLT3 inhibitors in acute myeloid leukemia: current status and future directions. Mol. Cancer Ther. 16, 991-1001.
<https://doi.org/10.1158/1535-7163.MCT-16-0876>
42. , R. A., Mandrekar, S. J., Huebner, L. J. et al. (2021) Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the alliance CALGB 10603/RATIFY trial. Leukemia 35, 2539-2551.
<https://doi.org/10.1038/s41375-021-01179-4>
43. , M. (2017) Midostaurin approved for FLT3-mutated AML. Blood 129, 3403-3406.
<https://doi.org/10.1182/blood-2017-05-782292>
44. , M., Small, D. (2003) FLT3: ITDoes matter in leukemia. Leukemia 17, 1738-1752.
<https://doi.org/10.1038/sj.leu.2403099>
45. , M. J. et al. (2024) Gilteritinib as post-transplant maintenance for AML with internal tandem duplication mutation of FLT3. J. Clin. Oncol. 42, 1766-1775.
<https://doi.org/10.1200/JCO.23.02474>
46. , W., Chao, C., Lin, C. et al. (2024) Efficacy and safety of second‑generation FLT3 inhibitors in acute myeloid leukemia: a systematic review and meta‑analysis of randomized controlled trials. Mol. Clin. Oncol. 21, 93.
<https://doi.org/10.3892/mco.2024.2791>
47. , Y., Xie, Q., Zhang, Z. et al. (2018) Protein kinase inhibitors for acute leukemia. Biomark. Res. 6, 8.
<https://doi.org/10.1186/s40364-018-0123-1>
48. , L. M., Hawes, B. E., van Biesen, T. et al. (1996) Role of c-Src tyrosine kinase in G protein-coupled receptor- and Gβγ subunit-mediated activation of mitogen-activated protein kinases. J. Biol. Chem. 271, 19443-19450.
<https://doi.org/10.1074/jbc.271.32.19443>
49. , M. C., Er, E. E., Blenis, J. (2011) The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem. Sci. 36, 320-328.
<https://doi.org/10.1016/j.tibs.2011.03.006>
50. , A., Shahriyary, F., Farrokhi, V. et al. (2024) A systematic review of second-generation FLT3 inhibitors for treatment of patients with relapsed/refractory acute myeloid leukemia. Leuk. Res. 141, 107505.
<https://doi.org/10.1016/j.leukres.2024.107505>
51. , H., Ro, S. W. (2021) Ras mitogen-activated protein kinase signaling and kinase suppressor of Ras as therapeutic targets for hepatocellular carcinoma. J. Liver Cancer 21, 1-11.
<https://doi.org/10.17998/jlc.21.1.1>
52. , M., Yokota, S., Iwai, T. et al. (1996) Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia. Leukemia 10, 1911-1918.
53. National Cancer Institute. Acute Myeloid Leukemia (AML) – Cancer Stat Facts. SEER Cancer Statistics. Retrieved from https://seer.cancer.gov/statfacts/html/amyl.html. Accessed November 5, 2024.
54. , C., Colita, A., Mitu, I. et al. (2023) A review of FLT3 kinase inhibitors in AML. J. Clin. Med. 12, 6429.
<https://doi.org/10.3390/jcm12206429>
55. , Y., Lax, I., Tomé, F. et al. (2014) Structure, domain organization, and different conformational states of stem cell factor-induced intact KIT dimers. Proc. Natl. Acad. Sci. U. S. A. 111, 1772-1777.
<https://doi.org/10.1073/pnas.1323254111>
56. , M. K., Mukhopadhyay, A. K. (2004) Tyrosine kinase – role and significance in cancer. Int. J. Med. Sci. 1, 101-115.
<https://doi.org/10.7150/ijms.1.101>
57. , A., Niroula, R. (2020) Acute myeloid leukemia: a review. R. I. Med. J. (2013) 103, 38-40.
58. , P., Chevallier, P., Knapper, S. et al. (2021) FLT3 ligand in acute myeloid leukemia: a simple test with deep implications. Leuk. Lymphoma 62, 264-270.
<https://doi.org/10.1080/10428194.2020.1834091>
59. , A., Maiuri, M. C., Zitvogel, L. et al. (2022) Trial watch: combination of tyrosine kinase inhibitors (TKIs) and immunotherapy. Oncoimmunology 11, 2077898.
<https://doi.org/10.1080/2162402X.2022.2077898>
60. , S., Bats, A. S., Coumoul, X. (2011) Understanding SOS (Son of Sevenless). Biochem. Pharmacol. 82, 1049-1056.
<https://doi.org/10.1016/j.bcp.2011.07.072>
61. , A., Verstovsek, S. (2013) Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clin. Cancer Res. 19, 1933-1940.
<https://doi.org/10.1158/1078-0432.CCR-12-0284>
62. , D. R., Wu, Y. M., Lin, S. F. (2000) The protein tyrosine kinase family of the human genome. Oncogene 19, 5548-5557.
<https://doi.org/10.1038/sj.onc.1203957>
63. , G. W., Griffiths, E. A. (2018) When to obtain genomic data in acute myeloid leukemia (AML) and which mutations matter. Blood Adv. 2, 3070-3080.
<https://doi.org/10.1182/bloodadvances.2018020206>
64. , M., Crucitta, S., Luculli, G. I. et al. (2024) Understanding mechanisms of resistance to FLT3 inhibitors in adult FLT3-mutated acute myeloid leukemia to guide treatment strategy. Crit. Rev. Oncol. Hematol. 201, 104424.
<https://doi.org/10.1016/j.critrevonc.2024.104424>
65. , P. P. (2019) Role of protein phosphatases in the cancer microenvironment. Biochim. Biophys. Acta Mol. Cell Res. 1866, 144-152.
<https://doi.org/10.1016/j.bbamcr.2018.07.006>
66. , C., Ayala, R., Larráyoz, M. J. et al. (2023) Molecular landscape and validation of new genomic classification in 2668 adult AML patients: real life data from the PETHEMA registry. Cancers (Basel) 15, 438.
<https://doi.org/10.3390/cancers15020438>
67. , T., Yang, X., Knapper, S. et al. (2011) FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood 117, 3286-3293.
<https://doi.org/10.1182/blood-2010-01-266742>
68. , C., Levy, D. E., Decker, T. (2007) JAK-STAT signaling: from interferons to cytokines. J. Biol. Chem. 282, 20059-20063.
<https://doi.org/10.1074/jbc.R700016200>
69. , R. F., Döhner, K., Krauter, J. et al. (2008) Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N. Engl. J. Med. 358, 1909-1918.
<https://doi.org/10.1056/NEJMoa074306>
70. , S., Fleischmann, M., Schnetzke, U. et al. (2020) Molecular mechanisms of resistance to FLT3 inhibitors in acute myeloid leukemia: ongoing challenges and future treatments. Cells 9, 2493.
<https://doi.org/10.3390/cells9112493>
71. , N. J., Daver, N., Dinardo, C. D. et al. (2024) Azacitidine, venetoclax, and gilteritinib in newly diagnosed and relapsed or refractory FLT3-mutated AML. J. Clin. Oncol. 42, 1499-1508.
<https://doi.org/10.1200/JCO.23.01911>
72. , H., Olipitz, W., Zebisch, A. et al. (2011) Therapy-related myeloid neoplasms: pathobiology and clinical characteristics. Br. J. Pharmacol. 162, 792-805.
<https://doi.org/10.1111/j.1476-5381.2010.01100.x>
73. Mali, R., Zhang, Q., DeFilippis, R. A. et al. (2021) Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models. Haematologica 106, 1034-1046.
74. , R. C., Sterner, R. M. (2021) CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 11, 69.
<https://doi.org/10.1038/s41408-021-00459-7>
75. , D. L., Radich, J. P. (2003) The role of FLT3 in haematopoietic malignancies. Nat. Rev. Cancer 3, 650-665.
<https://doi.org/10.1038/nrc1169>
76. , R. M., Mandrekar, S. J., Sanford, B. L. et al. (2017) Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N. Engl. J. Med. 377, 454-464.
<https://doi.org/10.1056/NEJMoa1614359>
77. , M., Cortes, J. E. (2023) Update on the role of gemtuzumab-ozogamicin in the treatment of acute myeloid leukemia. Ther. Adv. Hematol. 14, 20406207231154708.
<https://doi.org/10.1177/20406207231154708>
78. , S. (2011) Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications. J. Hematol. Oncol. 4, 13.
<https://doi.org/10.1186/1756-8722-4-13>
79. , S. (2023) Combination therapies with kinase inhibitors for acute myeloid leukemia treatment. Hematol. Rep. 15, 331-346.
<https://doi.org/10.3390/hematolrep15020035>
80. , S. S., Kornev, A. P. (2011) Protein kinases: evolution of dynamic regulatory proteins. Trends Biochem. Sci. 36, 65-77.
<https://doi.org/10.1016/j.tibs.2010.09.006>
81. Telios Pharma, Inc. (2023) TL-895 and KRT-232 study in acute myeloid leukemia. ClinicalTrials.gov. Retrieved from: https://clinicaltrials.gov/ct2/show/NCT04669067. Accessed: 5 November 2024.
82. , U., Pelosi, E., Castelli, G. (2021) Precision medicine treatment in acute myeloid leukemia is not a dream. Hemato 2, 131-153.
<https://doi.org/10.3390/hemato2010008>
83. , C., Steudel, C., Mohr, B. et al. (2002) Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99, 4326-4335.
<https://doi.org/10.1182/blood.V99.12.4326>
84. , P., Mooney, C. J., Brown, G. et al. (2017) The cytokine Flt3-ligand in normal and malignant hematopoiesis. Int. J. Mol. Sci. 18, 1115.
<https://doi.org/10.3390/ijms18061115>
85. , M. J., Stacey, M. M., Liu, B. A. et al. (2013) Molecular mechanisms of SH2- and PTB-domain-containing proteins in receptor tyrosine kinase signaling. Cold Spring Harbor Perspect. Biol. 5, a008987.
<https://doi.org/10.1101/cshperspect.a008987>
86. , T. L., Demaria, S., Rodriguez-Ruiz, M. E. et al. (2016) Emerging opportunities and challenges in cancer immunotherapy. Clin. Cancer Res. 22, 1845-1855.
<https://doi.org/10.1158/1078-0432.CCR-16-0049>
87. , A. (2003) Flt3 ligand: role in control of hematopoietic and immune functions of the bone marrow. News Physiol. Sci. 18, 247-251.
88. , M., Li, C., Zhu, X. (2018) FLT3 inhibitors in acute myeloid leukemia. J. Hematol. Oncol. 11, 133.
<https://doi.org/10.1186/s13045-018-0675-4>
89. , J., Friedman, R. (2023) Combination strategies to overcome drug resistance in FLT+ acute myeloid leukaemia. Cancer Cell Int. 23, 161.
<https://doi.org/10.1186/s12935-023-03000-x>
90. , X., Sexauer, A., Levis, M. (2014) Bone marrow stroma-mediated resistance to FLT3 inhibitors in FLT3-ITD AML is mediated by persistent activation of extracellular regulated kinase. Br. J. Haematol. 164, 61-72.
<https://doi.org/10.1111/bjh.12599>
91. , M., Muftuoglu, M., Short, N. J. et al. (2024) Phase I/II study of quizartinib, venetoclax, and decitabine triple combination in FLT3-ITD mutated AML. Blood 144 (Suppl. 1), 4263.
<https://doi.org/10.1182/blood-2024-204296>
92. , J. F., Vincent, B. G., Ivanova, A. et al. (2021) Phase II trial of pembrolizumab after high-dose cytarabine in relapsed/refractory acute myeloid leukemia. Blood Cancer Discov. 2, 616-629.
<https://doi.org/10.1158/2643-3230.BCD-21-0070>
93. , X., Gureasko, J., Shen, K. et al. (2006) An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125, 1137-1149.
<https://doi.org/10.1016/j.cell.2006.05.013>
94. Zhejiang ACEA Pharmaceutical Co. Ltd. (2025) A study to evaluate the STI-8591 in subjects with advanced acute myeloid leukemia (AML). ClinicalTrials.gov. Retrieved from: https://clinicaltrials.gov/ct2/show/NCT05947344. Accessed: 5 November 2024.
95. , R., Levis, M., Piloto, O. et al. (2004) FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood 103, 267-274.
<https://doi.org/10.1182/blood-2003-06-1969>
96. , R., Li, L., Nguyen, B. et al. (2021) FLT3 tyrosine kinase inhibitors synergize with BCL-2 inhibition to eliminate FLT3/ITD acute leukemia cells through BIM activation. Signal Transduct. Target. Ther. 6, 186.
<https://doi.org/10.1038/s41392-021-00578-4>
