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Abstract
Acute Myeloid Leukemia comprises a heterogeneous group of clonal disorders that result from the abnormal accumulation of immature myeloid cells within the bone marrow and peripheral blood. This study aims to detect Advances in the Molecular Pathogenesis of Acute Myeloid Leukemia. This has been elucidated by recent molecular studies that identified crucial mutations in FLT3, NPM1, and DNMT3A genes and epigenetic changes that contribute to leukemogenesis. Deregulated pathways besides PI3K/AKT and MAPK have also asserted themselves in disease progression and resistance to therapy. Hence, the review presents an extensive discussion of contemporary molecular perspectives of AML pathogenesis and their relevance to diagnosis and treatment. The rise in targeted therapies and precision medicine thus paints a promising clinical picture for a better prognosis. Knowledge of the biological compromise unleashed by mutations in genes and their interplay with the bone marrow microenvironment is key to forging newer therapies.
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Copyright (c) 2026 Rusul Ahmed Mohammed, Nada Khazal K. Hindi, Mustafa Hussein Mohammed, Zahraa I. J. Shubber, Abdolmajid Ghasemian (Author)

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References
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- Hochhaus A, La Rosée P. Imatinib therapy in chronic myelogenous leukemia. Leukemia. 2004;18(8):1321-1331. https://doi.org/10.1038/sj.leu.2403426
- Stanchina M, Soong D, Zheng-Lin B, Watts JM, Taylor J. Advances in AML therapies. Cancers (Basel). 2020;12(11):3225.
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- Huerga-Domínguez S, Villar S, Prósper F, Alfonso-Piérola A. Updates on AML management. Cancers (Basel). 2022;14(19):4756.
- Kantarjian HM, Kadia TM, DiNardo CD, Welch MA, Ravandi F. AML treatment outlook and MD Anderson approach. Cancer. 2021;127(8):1186-1207.
- Abaza Y, McMahon C, Garcia JS. Advancements and challenges in AML treatment. ASCO Educ Book. 2024;44(3):e438662.
- Bernasconi P, Borsani O. Targeting leukemia stem cell-niche dynamics. J Oncol. 2019;2019:8323592.
- Debnath A, Nath S. Prognosis and treatment in acute myeloid leukemia: a comprehensive review. Egypt J Med Hum Genet. 2024;25(1):91.
- Hofmann WK, Trumpp A, Müller-Tidow C. Therapy resistance mechanisms in hematological malignancies. Int J Cancer. 2023;152(3):340-347.
- Fajardo-Orduña GR, Ledesma-Martínez E, Aguiñiga-Sánchez I, Mora-García ML, Weiss-Steider B, Santiago-Osorio E. Inhibitors of chemoresistance pathways in AML. Int J Mol Sci. 2021;22(9):4955.
- Zeng AG, Bansal S, Jin L, Mitchell A, Chen WC, Abbas HA, et al. Cellular hierarchy in AML and drug response. Nat Med. 2022;28(6):1212-1223.
- Kühn MW, Pemmaraju N, Heidel FH. Epigenetic target molecules in myeloid cancers. Leukemia. 2025;39(8):1824-1837.
References
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Balducci L, Colloca G, Cesari M, Gambassi G. Assessment and treatment of elderly patients with cancer. Surg Oncol. 2010;19(3):117-123.
Tangchitpianvit K, Rattarittamrong E, Chai-Adisaksopha C, Piriyakhuntorn P, Rattanathammethee T, Hantrakool S, et al. Efficacy and safety of consolidation therapy with intermediate and high dose cytarabine in acute myeloid leukemia patients. Hematology. 2021;26(1):355-364.
Choi EJ, Lee JH, Kim H, Choi Y, Lee WS, Lee SM, et al. Autologous hematopoietic cell transplantation following high-dose cytarabine consolidation for core-binding factor-acute myeloid leukemia in first complete remission: a phase 2 prospective trial. Int J Hematol. 2021;113(6):851-860.
Kloosterman DJ, Akkari L. Macrophages at the interface of the co-evolving cancer ecosystem. Cell. 2023;186(8):1627-1651.
Duan H, Ren J, Wei S, Yang Z, Li C, Wang Z, et al. Integrated analyses of multi-omic data derived from paired primary lung cancer and brain metastasis reveal metabolic vulnerability as a novel therapeutic target. Genome Med. 2024;16(1):138.
Tayanloo-Beik A, Eslami A, Sarvari M, Jalaeikhoo H, Rajaeinejad M, Nikandish M, et al. Extracellular vesicles and cancer stem cells: a deadly duo in tumor progression. Oncol Rev. 2024;18:1411736.https://doi.org/10.3389/or.2024.1411736
Ntziachristos P, Abdel-Wahab O, Aifantis I. Emerging concepts of epigenetic dysregulation in hematological malignancies. Nat Immunol. 2016;17(9):1016-1024. https://doi.org/10.1038/ni.3517 .
Bănescu C, Tripon F, Muntean C. The genetic landscape of myelodysplastic neoplasm progression to acute myeloid leukemia. Int J Mol Sci. 2023;24(6):5734. https://doi.org/10.3390/ijms24065734 .
Mahmud M, Vasireddy S, Gowin K, Amaraneni A. Myeloproliferative neoplasms: contemporary review and molecular landscape. Int J Mol Sci. 2023;24(24):17383. https://doi.org/10.3390/ijms242417383
Bewersdorf JP, Abdel-Wahab O. Translating recent advances in the pathogenesis of acute myeloid leukemia to the clinic. Genes Dev. 2022;36(5-6):259-277. https://doi.org/10.1101/gad.349368.122
Charrot S, Armes H, Rio-Machin A, Fitzgibbon J. AML through the prism of molecular genetics. Br J Haematol. 2020;188(1):49-62. https://doi.org/10.1111/bjh.16356
Creutzig U, Zimmermann M, Reinhardt D, Rasche M, von Neuhoff C, Alpermann T, et al. Changes in cytogenetics and molecular genetics in acute myeloid leukemia from childhood to adult age groups. Cancer. 2016;122(24):3821-3830. https://doi.org/10.1002/cncr.30220
Picimbon JF. A new view of genetic mutations. Australas Med J. 2017;10(8):701.
Williams SC. Genetic mutations you want. Proc Natl Acad Sci U S A. 2016;113(10):2554-2557. https://doi.org/10.1073/pnas.1601663113
Treviño LS, Wang Q, Walker CL. https://doi.org/10.1016/j.pbiomolbio.2015.02.013 . Prog Biophys Mol Biol. 2015;118(1-2):8-13.
Yang Y, Kim H, Li W, Kong AN. Natural compound-derived epigenetic regulators targeting epigenetic readers, writers and erasers. Curr Top Med Chem. 2016;16(7):697-713. https://doi.org/10.2174/1568026615666150826114359
Gray JS, Wani SA, Campbell MJ. Epigenomic alterations in cancer: mechanisms and therapeutic potential. Clin Sci (Lond). 2022;136(7):473-492.
Chen Z, Natarajan R. Epigenetic modifications in metabolic memory: what are the memories, and can we erase them? Am J Physiol Cell Physiol. 2022;323(2):C570-C582. https://doi.org/10.1152/ajpcell.00201.2022
Popov P, Jurkowska RZ. Beyond genes: a clinician's guide to epigenetics. Breathe. 2025;21(4). https://doi.org/10.1183/20734735.0227-2024
Medyouf H. The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications. Blood. 2017;129(12):1617-1626. https://doi.org/10.1182/blood-2016-11-696070
Bakhtiyari M, Liaghat M, Aziziyan F, Shapourian H, Yahyazadeh S, Alipour M, et al. The role of bone marrow microenvironment cells in acute myeloid leukemia progression. Cell Commun Signal. 2023;21(1):252.
Mendes M, Monteiro AC, Neto E, Barrias CC, Sobrinho-Simoes MA, Duarte D, et al. Transforming the niche: the emerging role of extracellular vesicles in acute myeloid leukaemia progression. Int J Mol Sci. 2024;25(8):4430. https://doi.org/10.3390/ijms25084430
Wang A, Zhong H. Roles of the bone marrow niche in hematopoiesis, leukemogenesis, and chemotherapy resistance in acute myeloid leukemia. Hematology. 2018;23(10):729-739. https://doi.org/10.1080/10245332.2018.1486064
Giallongo S, Duminuco A, Dulcamare I, Zuppelli T, La Spina E, Scandura G, et al. Engagement of mesenchymal stromal cells in the remodeling of the bone marrow microenvironment. Biomolecules. 2023;13(12):1701. https://doi.org/10.3390/biom13121701
Kouroukli O, Symeonidis A, Foukas P, Maragkou MK, Kourea EP. Bone marrow immune microenvironment in myelodysplastic syndromes. Cancers (Basel). 2022;14(22):5656. https://doi.org/10.3390/cancers14225656
Pimenta DB, Varela VA, Datoguia TS, Caraciolo VB, Lopes GH, Pereira WO. The bone marrow microenvironment mechanisms in acute myeloid leukemia. Front Cell Dev Biol. 2021;9:764698.
Naji NS, Sathish M, Karantanos T. Inflammation and related signaling pathways in acute myeloid leukemia. Cancers (Basel). 2024;16(23):3974. https://doi.org/10.3390/cancers16233974
Chakraborty S, Park CY. Pathogenic mechanisms in acute myeloid leukemia. Curr Treat Options Oncol. 2022;23(11):1522-1534. https://doi.org/10.1007/s11864-022-01021-8
Medina KL. Flt3 signaling in B lymphocyte development and humoral immunity. Int J Mol Sci. 2022;23(13):7289.
Niemitz E. Ras pathway activation in breast cancer. Nat Genet. 2013;45(11):1273. https://doi.org/10.1038/ng.2817
Loboda A, Nebozhyn M, Klinghoffer R, Frazier J, Chastain M, Arthur W, et al. BMC Med Genomics. 2010;3(1):26. https://doi.org/10.1186/1755-8794-3-26
Newell P, Toffanin S, Villanueva A, Chiang DY, Minguez B, Cabellos L, et al. Ras pathway activation in hepatocellular carcinoma. J Hepatol. 2009;51(4):725-733.
Philips RL, Wang Y, Cheon H, Kanno Y, Gadina M, Sartorelli V, et al. The JAK-STAT pathway at 30: Much learned, much more to do. Cell. 2022;185(21):3857-3876. https://doi.org/10.1016/j.cell.2022.09.023
Allegra A, Alonci A, Penna G, Innao V, Gerace D, Rotondo F, et al. The cancer stem cell hypothesis: a guide to potential molecular targets. Cancer Invest. 2014;32(9):470-495. https://doi.org/10.3109/07357907.2014.958231
Jean G. Comparative genomic profiling of CEBPA, NPM1, IDH1, and RUNX1 mutations across leukemia subtypes. 2025.
Sendker S, Reinhardt D, Niktoreh N. Redirecting the immune microenvironment in acute myeloid leukemia. Cancers (Basel). 2021;13(6):1423. https://doi.org/10.3390/cancers13061423
Tufail M, Jiang CH, Li N. Immune evasion in cancer: mechanisms and therapeutic approaches. Signal Transduct Target Ther. 2025;10(1):227. https://doi.org/10.1038/s41392-025-02280-1
Chen Y, Wang J, Zhang F, Liu P. Immunotherapy for acute myeloid leukemia: advances and challenges. Front Pharmacol. 2023;14:1151032.
Murphy T, Yee KW. Cytarabine and daunorubicin for AML treatment. Expert Opin Pharmacother. 2017;18(16):1765-1780.
Weinberg OK, Porwit A, Orazi A, Hasserjian RP, Foucar K, Duncavage EJ, et al. International Consensus Classification of AML. Virchows Arch. 2023;482(1):27-37.
Qiao D, Wang RC, Wang Z. Precision oncology: current landscape and future perspectives. Cells. 2025;14(22):1804. https://doi.org/10.20944/preprints202510.1139.v1
Wang J, Tomlinson B, Lazarus HM. Update on small molecule targeted therapies for AML. Curr Treat Options Oncol. 2023;24(7):770-801. https://doi.org/10.1007/s11864-023-01090-3
Szelest M, Giannopoulos K. Targeting splicing for hematological malignancies therapy. BMC Genomics. 2024;25(1):1067. https://doi.org/10.1186/s12864-024-10975-y
Hochhaus A, La Rosée P. Imatinib therapy in chronic myelogenous leukemia. Leukemia. 2004;18(8):1321-1331. https://doi.org/10.1038/sj.leu.2403426
Stanchina M, Soong D, Zheng-Lin B, Watts JM, Taylor J. Advances in AML therapies. Cancers (Basel). 2020;12(11):3225.
Short NJ, Konopleva M, Kadia TM, Borthakur G, Ravandi F, DiNardo CD, et al. Advances in AML treatment: new drugs and challenges. Cancer Discov. 2020;10(4):506-525.
Joshi DC, Sharma A, Prasad S, Singh K, Kumar M, Sherawat K, et al. Novel therapeutic agents in clinical trials. Discov Oncol. 2024;15(1):342.
Adeyemi SA, Ngema LM, Choonara YE. Advances in targeted therapies for blood cancer. RSC Pharm. 2025;2(5):950-961. https://doi.org/10.1039/d5pm00090d/v1/review2
Tothova Z, Valton AL, Gorelov RA, Vallurupalli M, Krill-Burger JM, Holmes A, et al. Cohesin mutations in MDS/AML. JCI Insight. 2021;6(3):e142149.
Huerga-Domínguez S, Villar S, Prósper F, Alfonso-Piérola A. Updates on AML management. Cancers (Basel). 2022;14(19):4756.
Kantarjian HM, Kadia TM, DiNardo CD, Welch MA, Ravandi F. AML treatment outlook and MD Anderson approach. Cancer. 2021;127(8):1186-1207.
Abaza Y, McMahon C, Garcia JS. Advancements and challenges in AML treatment. ASCO Educ Book. 2024;44(3):e438662.
Bernasconi P, Borsani O. Targeting leukemia stem cell-niche dynamics. J Oncol. 2019;2019:8323592.
Debnath A, Nath S. Prognosis and treatment in acute myeloid leukemia: a comprehensive review. Egypt J Med Hum Genet. 2024;25(1):91.
Hofmann WK, Trumpp A, Müller-Tidow C. Therapy resistance mechanisms in hematological malignancies. Int J Cancer. 2023;152(3):340-347.
Fajardo-Orduña GR, Ledesma-Martínez E, Aguiñiga-Sánchez I, Mora-García ML, Weiss-Steider B, Santiago-Osorio E. Inhibitors of chemoresistance pathways in AML. Int J Mol Sci. 2021;22(9):4955.
Zeng AG, Bansal S, Jin L, Mitchell A, Chen WC, Abbas HA, et al. Cellular hierarchy in AML and drug response. Nat Med. 2022;28(6):1212-1223.
Kühn MW, Pemmaraju N, Heidel FH. Epigenetic target molecules in myeloid cancers. Leukemia. 2025;39(8):1824-1837.
