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Transcriptome of MLL-AF9 blast sensitive and resistant to chemotherapy

ABSTRACT: Chemotherapy resistance in acute myeloid leukemia (AML) remains a significant challenge, and understanding its molecular basis is crucial. Using multi-omic profiling and in vivo functional genomics, we identified splicing perturbations as a major determinant of chemoresistance in AML. We pinpointed a splicing-associated network involving the splicing regulator SRRM1 and two kinases, CLK and PAK1, as critical vulnerabilities in chemoresistant AML cells. Both kinases are hyperactivated in chemoresistant AML cells and we discovered a point variant in PAK1, c.1429G>T p.(Ala477Ser), that conferred resistance to chemotherapy in a patient undergoing relapse post-treatment. Combinatory inhibition of PAK1 and CLK kinases exhibited partially similar splicing perturbations to SRRM1 loss, preferentially targeting chemoresistant AML cell lines, primary cells, and multiple mouse models of AML and potentiating anti-leukemic effects of chemotherapy. Our study provides a new therapeutic rationale for targeting this splicing network to circumvent AML patient relapse and maximize the therapeutic benefit of chemotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE244761 | GEO | 2026/07/09

REPOSITORIES: GEO

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Project description:Acute Myeloid Leukemia (AML) commonly relapses after initial chemotherapy response. We assessed metabolic adaptations in a minimal-residual disease setting of chemoresistant cells in vivo before overt relapse, identifying elevated branched-chain amino acid (BCAA) levels in patient-derived xenografts (PDX) and immunophenotypically identified leukemia stem cells from AML patients. Notably, this was associated with increased BCAA transporter expression without indications for higher BCAA catabolism. Restricting of BCAAs further reduced chemoresistant AML cells but relapse still occurred. Among the persisting cells we found an unexpected Acute Myeloid Leukemia (AML) commonly relapses after initial chemotherapy response. We assessed metabolic adaptations in chemoresistant cells in vivo before overt relapse, identifying altered branched-chain amino acid (BCAA) levels in patient-derived xenografts (PDX) and immunophenotypically identified leukemia stem cells from AML patients. Notably, this was associated with increased BCAA transporter expression with low BCAA catabolism. Restricting of BCAAs further reduced chemoresistant AML cells but relapse still occurred. Among the persisting cells we found an unexpected increase in protein production. This was accompanied by elevated translation of 2-oxoglutarate-and-iron-dependent oxygenase 1 (OGFOD1), a known ribosomal dioxygenase that adjusts the fidelity of tRNA anticodon pairing with coding mRNA1–3 and upregulates protein synthesis in AML driving disease aggressiveness. Inhibiting OGFOD1 impaired translation processing, decreased protein synthesis and improved animal survival even with chemoresistant AML through regulation of protein synthesis. Leukemic cells can therefore persist despite the stress of chemotherapy and nutrient deprivation through adaptive control of translation while sparing normal hematopoiesis. Targeting OGFOD1 may offer a distinctive, translation modifying means of reducing the chemopersisting cells that drive relapse.

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Transcriptome of MLL-AF9 blast sensitive and resistant to chemotherapy

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