Emerging research has shed new light on the molecular mechanisms underlying acute myeloid leukemia (AML), highlighting particularly pernicious forms driven by specific oncogenic drivers combined with aberrant signaling pathways. A recent landmark study published in Nature Communications propels our understanding forward by uncovering how thrombopoietin—a key hematopoietic growth factor—enhances susceptibility to AML characterized by the coexistence of EVI1 and KMT2A-MLLT3 oncogenic alterations. This form of AML is notorious for its aggressive clinical course and poor patient outcome, driven in part by the expression of stem cell gene programs that sustain leukemic propagation and therapy resistance.
Thrombopoietin (TPO) has classically been recognized for its role in regulating megakaryopoiesis and platelet production via binding to the MPL receptor. However, the study in question elucidates a more sinister role of thrombopoietin in hematologic malignancies by promoting leukemogenesis in genetically predisposed contexts. The investigators demonstrate that TPO exposure significantly enhances the leukemic transformation potential in cellular models harboring simultaneous EVI1 overexpression and the KMT2A-MLLT3 gene fusion—two molecular aberrations independently associated with poor prognosis in AML.
The molecular interplay between EVI1 and the KMT2A-MLLT3 fusion protein represents a crucial nexus in leukemogenesis. EVI1, encoded by the MECOM locus, functions as a transcription factor intimately involved in stem cell self-renewal pathways and epigenetic regulation. Dysregulated EVI1 expression has been consistently identified in therapy-resistant AML, correlating with adverse clinical outcomes. Meanwhile, the KMT2A-MLLT3 fusion originates from chromosomal translocation events t(9;11), which engender aberrant gene expression profiles fostering malignant proliferation.
Leveraging advanced single-cell transcriptomic analyses, the authors confirmed that AML cells co-expressing EVI1 and KMT2A-MLLT3 exhibit a heightened activation of stemness gene signatures. These gene programs are characterized by enhanced self-renewal capacity, metabolic plasticity, and evasion of differentiation cues, contributing to the aggressive phenotype and therapeutic refractoriness encountered in patients. Strikingly, thrombopoietin signaling was shown to amplify these stem cell-associated transcriptional networks, further potentiating leukemia-initiating cell properties.
Mechanistically, thrombopoietin acts through MPL receptor engagement, initiating downstream JAK-STAT, PI3K-AKT, and MAPK signaling cascades. The study’s data revealed that in the presence of EVI1+KMT2A-MLLT3 oncogenic drivers, these pathways synergize to remodel the chromatin landscape, enhancing accessibility at stemness gene loci and driving persistent oncogenic transcription. This molecular choreography underscores the dynamic crosstalk between extrinsic hematopoietic cytokine signals and intrinsic leukemic transcriptional regulators.
In vivo modeling through murine xenotransplantation further substantiated these findings. AML cells exposed to thrombopoietin prior to engraftment exhibited increased leukemic burden, accelerated disease progression, and diminished survival in recipient mice. Functional assays demonstrated that thrombopoietin stimulation augmented leukemia stem cell frequency, a critical reservoir implicated in relapse and treatment failure. These results spotlight thrombopoietin as a potential amplifier of leukemic aggressiveness rather than a mere supporting hematopoietic factor.
Therapeutically, the revelation that thrombopoietin signaling exacerbates EVI1+KMT2A-MLLT3-driven AML provides a novel avenue for targeted intervention. Pharmacologic inhibition of MPL receptor signaling demonstrated attenuation of leukemic stem cell maintenance and restored sensitivity to chemotherapeutic agents in preclinical models. These promising outcomes advocate for the development of combination therapies aimed at disrupting cytokine-mediated stemness reinforcement in refractory AML subsets.
The implications of this research extend beyond the immediate molecular insights to influence clinical management strategies for high-risk AML. Identification of thrombopoietin’s pathogenic role facilitates risk stratification of patients based on TPO concentration and MPL receptor expression profiles. This precision medicine approach could inform treatment intensification or enrollment in clinical trials evaluating MPL antagonists or JAK-STAT pathway inhibitors, potentially improving survival outcomes.
Furthermore, the study advances our conceptual understanding of how microenvironmental factors contribute to leukemic evolution and disease heterogeneity. Thrombopoietin produced in the bone marrow niche not only supports normal hematopoiesis but, in genetically susceptible contexts, acts as a driver of malignant stem cell fitness. This paradigm urges a reevaluation of cytokine biology in hematologic cancers, emphasizing the dualistic roles of growth factors in health and disease.
From a biomolecular perspective, the integration of EVI1 and KMT2A-MLLT3 oncogenic signaling with thrombopoietin pathways orchestrates a transcriptional program reminiscent of embryonic stem cells, conferring plasticity and survival advantage to leukemic cells. Targeting this stem cell-like state may represent the fulcrum for eradicating minimal residual disease, a primary failure point in AML therapy. Epigenetic modulators capable of reversing chromatin accessibility changes induced by thrombopoietin exposure represent an intriguing therapeutic avenue worth exploration.
The study also points to potential biomarkers for early detection and therapeutic monitoring. Elevated TPO levels, coupled with gene expression profiles denoting EVI1 and KMT2A-MLLT3 activity, could serve as indicators of impending disease progression or relapse, prompting timely clinical intervention. Developments in liquid biopsy techniques might allow for non-invasive longitudinal assessment of these parameters, refining patient management.
In conclusion, the research by Châtel-Soulet and colleagues marks a significant milestone in unraveling the complex biology of AML driven by combined EVI1 overexpression and KMT2A-MLLT3 fusion. Their discovery that thrombopoietin potentiates leukemic stemness and progression reshapes our understanding of cytokine involvement in cancer and fosters new therapeutic possibilities. This study underscores the necessity for integrated molecular and microenvironmental targeting to combat refractory leukemia effectively.
As the AML research community continues to decode the intricate gene-environment interactions that fuel malignancy, findings such as these catalyze progress toward curative treatments. Future investigations will need to elucidate the full spectrum of cytokine interactions influencing leukemic stem cell niches and further develop targeted agents to disrupt these pathogenic circuits. Ultimately, translating these insights into clinical breakthroughs holds promise for improving prognosis in AML patients burdened with the most aggressive disease subtypes.
Subject of Research: Molecular mechanisms underlying acute myeloid leukemia driven by EVI1 overexpression and KMT2A-MLLT3 fusion, and the role of thrombopoietin in enhancing disease aggressiveness.
Article Title: Thrombopoietin increases susceptibility for EVI1 + KMT2A-MLLT3-driven AML expressing stem cell genes linked to poor outcome.
Article References:
Châtel-Soulet, HÉ., Juge, S., Pereira, A.L. et al. Thrombopoietin increases susceptibility for EVI1 + KMT2A-MLLT3-driven AML expressing stem cell genes linked to poor outcome. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67611-w
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Tags: aggressive forms of AMLEVI1 and KMT2A-MLLT3 oncogenic alterationshematopoietic growth factors in cancerleukemogenesis in genetically predisposed individualsmegakaryopoiesis and platelet productionmolecular mechanisms of AMLNature Communications study onpoor prognosis in AML patientsstem cell gene programs in leukemiatherapy resistance in acute myeloid leukemiaThrombopoietin role in acute myeloid leukemiatranscription factors in leukemogenesis
