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Hierarchical Lineage Tracing Reveals Diverse Pathways of AML Treatment Resistance [scRNA-seq]

ABSTRACT: Cancer cells adapt to treatment, leading to the emergence of clones that are more aggressive and resistant to anti-cancer therapies. We have a limited understanding of the evolution of treatment resistance as we have lacked technologies to map the evolution of cancer under the selective pressures. To address this, we developed a hierarchical, dynamic lineage tracing method called FLARE (Following Lineage Adaptation and Resistance Evolution). We use this technique to track the progression of acute myeloid leukemia (AML) cell lines through exposure to Cytarabine (AraC), a front-line treatment in AML, in vitro and in vivo. We map distinct cellular lineages in murine and human AML cell lines that are predisposed to AraC persistence and/or resistance via upregulation of cell adhesion and motility pathways. Additionally, we highlight heritable increased expression of immunoproteasome 11S regulatory cap subunits as a potential mechanism aiding AML cell survival, proliferation, and immune escape in vivo. Finally, we validate the clinical relevance of these signatures in the TARGET-AML cohort, with a bisected response in blood and bone marrow. Our findings reveal a broad spectrum of resistance signatures attributed to significant cell transcriptional changes, and we expect this high-resolution profiling of treatment response to be a useful tool to dissect the evolution of treatment response in a wide range of tumor types.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE289454 | GEO | 2025/02/12

REPOSITORIES: GEO

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Hierarchical Lineage Tracing Reveals Diverse Pathways of AML Treatment Resistance [DNA-seq]

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Loss of DKM6A confers drug resistance in acute myeloid leukemia (ChIP-seq of AML cell lines K562 and THP-1)

Project description:Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm resulting from the malignant transformation of myeloid progenitors. Despite intensive chemotherapy leading to initial treatment responses, relapse caused by intrinsic or acquired drug resistance represents a major challenge. Here, we report that histone 3 lysine 27 demethylase KDM6A (UTX) is targeted by inactivating mutations and mutation-independent regulation in relapsed AML. Analyses of matched diagnosis and relapse specimens from individuals with KDM6A mutations showed an outgrowth of the KDM6A mutated tumor population at relapse. KDM6A-null myeloid leukemia cells were more resistant to treatment with the chemotherapeutic agents cytarabine (AraC) and daunorubicin. Inducible re-expression of KDM6A in KDM6A-null cell lines suppressed proliferation and sensitized cells again to AraC treatment. RNA expression analysis and functional studies revealed that resistance to AraC was conferred by downregulation of the nucleoside membrane transporter ENT1 (SLC29A1). Our results show that loss of KDM6A provides cells with a selective advantage during chemotherapy, which ultimately leads to the observed outgrowth of clones with KDM6A mutations or reduced KDM6A expression at relapse.

2019-06-18 | GSE128261 | GEO

Loss of DKM6A confers drug resistance in acute myeloid leukemia (ChIP-seq of AML cell lines MM-1 and MM-6)

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Down-regulation of MTSS1 is associated with a poor prognosis in acute myeloid leukemia and differentially affects responses to different drugs

Project description:Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic cells. Despite recent approvals of targeted drugs, chemotherapy with cytosine arabinoside (araC) and an anthracycline like daunorubicin remains an important pillar of treatment. In a previous work, we have shown that MTSS1 is down-regulated at relapse compared to diagnosis of AML and its down-regulation was previously implicated in aggressiveness of solid tumors. Our results showed that MTSS1 expression was regulated by methylation and reduced by araC and daunorubicin. Experimental down-regulation rendered human AML cell lines more resistant to araC, daunorubicin, and eight additional drugs. In contrast, venetoclax, a BCL2 inhibitor, was more effective towards cells with low MTSS1 expression. A CRISPR/Cas9-mediated knock-out of the MTSS1 gene was used to generate insight into the molecular changes induced by the down-regulation of MTSS1. The knock-out led to the deregulation of > 900 genes which included numerous target genes of transcription factors with a confirmed role in hematopoiesis and AML. A gene ontology analysis of the differentially expressed genes revealed that genes linked to transcription, cell cycle, and immune response were strongly affect. In summary, down-regulation of MTSS1 is associated with primary and secondary chemotherapy resistance in AML. In experimental models, it confers refractoriness to several cytotoxic drugs, yet sensitizes cells to venetoclax, pointing towards ways to overcome therapy resistance in MTSS1low AML.

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Expression data from human AML blasts and healthy CD34+ bone marrow cells

Project description:Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the bone marrow (BM) stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Iradubicin (standard AML chemotherapy) by interfering with the BM stroma-mediated chemoresistance. We report that lenalidomide and pomalidomide have cytotoxic effects on neither AML cells nor BM-MSCs, but they increase the immunosuppressive/immunomodulatory properties of BM-MSCs. When combined with AraC and Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of AML cells in vitro and in vivo but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide highly mobilizes AML cells, but not healthy CD34+ cells, to peripheral blood (PB) likely through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated AML blasts but not in CD34+ cells. Collectively, IMiDs mobilize AML blasts to PB through downregulation of CXCR4 but do not improve AraC/Idarubicin activity in a preclinical model of AML.

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