KMT2A oncoproteins induce epigenetic resistance to targeted therapies.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1060315 | ENA |
REPOSITORIES: ENA
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Project description:Chromosomal translocations involving the Lysine-Methyl-Tansferase-2A (KMT2A) locus generate potent oncogenes that cause highly aggressive acute leukemias KMT2A and the most frequent translocation partners encode proteins that interact with DNA to regulate developmental gene expression. KMT2A-oncogenic fusion proteins (oncoproteins) contribute to the epigenetic mechanisms that allow KMT2A-rearranged leukemias to evade targeted therapies. By profiling the oncoprotein-target sites of 34 KMT2A-rearranged leukemia samples, we find that the genomic enrichment of oncoprotein binding is highly variable between samples. At high levels of expression, the oncoproteins preferentially activate either the lymphoid or myeloid lineage program depending on the fusion partner. These fusion-partner-dependent binding sites correspond to the frequencies of each mutation in acute lymphoid leukemia versus acute myeloid leukemia. By profiling a sample that underwent a lymphoid-to-myeloid lineage switching event in response to lymphoid-directed treatment, we find the global oncoprotein levels are reduced and the oncoprotein-target gene network changes. At lower levels of expression, the oncoprotein shifts to a non-canonical regulatory program that favors the myeloid lineage, and in a subset of resistant patients, the Menin inhibitor Revumenib induces a similar response. The dynamic shifts in KMT2A oncoproteins we describe likely contribute to epigenetic resistance of KMT2A-rearranged leukemias to targeted therapies.
2024-09-27 | GSE252378 | GEO
Project description:Activating mutations in kinase/PI3K/RAS signaling pathways are common in acute leukemia with KMT2A rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remain unclear. Using a retroviral acute myeloid leukemia model, we demonstrate that NRASG12D, FLT3ITD, and FLT3N676K accelerates KMT2A-MLLT3 leukemia onset. Importantly, also the presence of subclonal FLT3N676K in KMT2A-R leukemic cells shorten disease latency, possibly by providing stimulatory factors such as Mif. Acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 were identified in KMT2A-MLLT3 driven leukemia and favored clonal expansion. KMT2A-MLLT3 leukemia with an activating mutation enforce Myc- and Myb transcriptional modules, whereas KMT2A-MLLT3 leukemias lacking activating mutations displayed upregulation of signal transduction pathways. Our results provide new insight into the biology of KMT2A-R leukemia and highlights the importance of activated signaling as a contributing driver in this disease.
2018-05-02 | PXD008213 | Pride
Project description:Bromo- and extra-terminal domain inhibitors (BETi) have exhibited therapeutic activities in many cancers, including KMT2A-rearranged (KMT2A-r) leukemia, in preclinical studies. However, the mechanisms controlling BETi response and resistance are poorly understood. We conducted genome-wide loss-of-function CRISPR screens using BETi-treated KMT2A-r cell lines. SPOP gene deficiency caused significant BETi resistance, which was further validated in cell line and xenograft models. In SPOP-knockout KMT2A-r leukemia cells, TRIM24 was identified as a SPOP substrate that mediates resistance to BETi. Additionally, proteomics analysis and a kinase-vulnerability CRISPR screen indicated that resistant cells are sensitive to GSK3 inhibition. Genetically perturbating TRIM24 or pharmaceutical inhibition of its downstream target GSK3 in SPOP-knockout cells reversed the BETi-resistance phenotype. A combination therapy regimen inhibiting both BET and GSK3 impeded leukemia progression in patient-derived xenografts in vivo. Our results revealed not only novel molecular mechanisms underlying BETi resistance but also a promising strategy for treating KMT2A-r leukemia.
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Project description:Acute myeloid leukemia (AML) is a disease with poor outcome but patients harbouring certain chromosomal rearrangements or complex karyotypes have particularly adverse prognosis. For these patients, targeted therapies have not yet made a significant clinical impact. To understand the molecular landscape of poor risk AML we profiled 55 poor risk AML patients using a multiomics approach that included transcriptomics (n=39), proteomics (n=55), phosphoproteomics (n=55) and an ex vivo drug sensitivity screening (482 compounds tested in at least 30 patients). We identified a phosphoproteomics signature that define two biologically distinct groups of KMT2A rearranged leukaemia, which we term MLLGA and MLLGB. MLLGA presented increased DOT1L phosphorylation, HOXA gene expression, CDK1 activity and phosphorylation of proteins involved in RNA metabolism, replication and DNA damage when compared to MLLGB and no KMT2A rearranged samples. MLLGA was particularly sensitive to 15 compounds including genotoxic drugs and inhibitors of mitotic kinases and IMPDH relative to other cases. The expression of IMPDH2 and multiple nucleolar proteins was higher in MLLGA and correlated with the response to IMPDH inhibition in KMT2A rearranged leukaemia, suggesting a role of the nucleolar activity in sensitivity to IMPDH inhibition. In summary, our multilayer molecular profiling of poor risk AML matched to the response to hundreds of compounds identified a phosphoproteomics signature that define two biologically and phenotypically distinct groups of KMT2A rearranged leukaemia. These data provide a rationale for the development of specific therapies for KMT2A subgroups characterised by the MLLGA phosphoproteomics signature identified in this study.
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Project description:Identification of clinical combination therapies to induce durable responses in kidney cancers
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Project description:Acute myeloid leukemias (AML) patients bearing chromosomal rearrangements of KMT2A or MLL gene (KMT2A -r) have poor overall survival. Recently, compounds targeting the KMT2A fusion protein complex, such as DOT1L and Menin inhibitors, have shown promising pre-clinical efficacy. Yet, molecular regulators of the anti-tumor activities of these agents remain poorly studied. UTX is a histone H3K27 demethylase with recurrent loss-of-function mutations in human cancers including leukemia. UTX-null leukemia shows greater resistance to chemotherapy agents. However, the impact of UTX on drug resistance of KMT2A -r AML has not been explored. Through a epigenetic compound screen, we identified a unique role of UTX in the regulation of DOT1L and Menin therapies in KMT2A-r AML. Loss of UTX confers resistance to DOT1L and Menin inhibition in an MLL target gene-independent manner. Mechanistically, We show that UTX is required for activation of myeloid differentiation programs induced by DOT1L inhibition. We also revealed BCL2A1 as a target of UTX. Depletion of UTX increased vulnerability to BCL2 inhibitor venetoclax in vitro and in vivo, and combinational treatment of venetoclax could overcome the therapeutic resistance to DOT1L inhibition caused by UTX loss. Our study provides new insights into the role of UTX in therapeutic responses in KMT2A-r AML.
2022-11-01 | GSE214275 | GEO
Project description:Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR/Cas9-based gene-editing studies. We observed that myeloma cell resistance to "degraders" of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; involves loss-of-function for the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex. The substantial gene-level differences for CRBN- vs. VHL-based degraders explains mechanistically the lack of cross-resistance for degraders targeting the same protein via different E3 ligase/CRLs.
2021-02-12 | GSE162205 | GEO
Project description:Divergent resistance mechanisms to HER2-targeted therapies in breast cancer
2021-04-21 | GSE161422 | GEO
Project description:Divergent resistance mechanisms to HER2-targeted therapies in breast cancer
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Project description:KMT2A-rearranged acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia which represents the most common form diagnosed in infancy. Oncogenic KMT2A-fusion proteins recruit histone methyltransferase DOT1L which leads to misplaced H3K79 methylation inducing an abnormal transcriptomic landscape that favors leukemia development. Hence, inhibition of DOT1L represents an attractive therapeutic strategy. Unfortunately, the first-in-class DOT1L inhibitor pinometostat resulted in the development of resistance. To understand this resistance we established acquired resistance to DOT1L inhibition in a pediatric KMT2A::AFF1+ B-ALL cell line model that stably became ~35-fold more resistant to pinometostat. Interestingly, while becoming almost completely independent of DOT1L-mediated H3K79 methylation, these cells remained fully dependent on the physical presence of DOT1L, HOXA9, as well as the KMT2A::AFF1 fusion protein. Further characterization of these cells using RNA-, ChIP-, and ATAC-sequencing analyses revealed that acquired resistance to DOT1L inhibition leads to a selective loss of KMT2A-fusion driven epigenetic regulation and expression of genes such as PROM1 (encoding the hematopoietic/leukemia stem cell marker CD133) and its enhancer TAPT1, as well as other putative KMT2A::AFF1 target genes such as RUNX2, PRSS12, ZC3H12, and GNAQ. In contrast, the levels of H3K79me2 and expression of other KMT2A::AFF1 target genes, including HOXA9, MEIS1, and CDK6 remained unaffected. Concomitantly, pinometostat-resistant KMT2A::AFF1+ B-ALL cells showed upregulation of genes associated with a myeloid immunophenotype, including CD33, LILRB4/CD85k, MPEG1, CCL5, and LIMK1. Taken together, we here present a valuable model to study the adaptive potential of KMT2A-rearranged ALL upon losing dependency on one of its main oncogenic properties.
2023-09-27 | GSE230806 | GEO