Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE230807 | GEO | 2023/09/27
REPOSITORIES: GEO
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Project description:In KMT2A-rearranged acute lymphoblastic leukemia (ALL), an aggressive malignancy, oncogenic KMT2A-fusion proteins inappropriately recruit DOT1L to promote leukemogenesis, highlighting DOT1L as an attractive therapeutic target. Unfortunately, treatment with the first-in-class DOT1L inhibitor pinometostat eventually leads to non-responsiveness. To understand this we established acquired pinometostat resistance in pediatric KMT2A::AFF1+ B-ALL cells. Interestingly, these cells became mostly independent of DOT1L-mediated H3K79 methylation, but still relied on the physical presence of DOT1L, HOXA9 and the KMT2A::AFF1 fusion. Moreover, these cells selectively lost the epigenetic regulation and expression of various KMT2A-fusion target genes such as PROM1/CD133, while other KMT2A::AFF1 target genes, including HOXA9 and CDK6 remained unaffected. Concomitantly, these pinometostat-resistant cells showed upregulation of several myeloid-associated genes, including CD33 and LILRB4/CD85k. Taken together, this model comprehensively shows the adaptive potential of KMT2A-rearranged ALL cells upon losing dependency on one of its main oncogenic properties.
| S-EPMC10517487 | biostudies-literature
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
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 | GSE230799 | GEO
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 | GSE230791 | GEO
Project description:Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’
| PRJNA962684 | ENA
Project description:Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [ATAC-seq]
| PRJNA962578 | ENA
Project description:Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [ChIP-seq]
| PRJNA962573 | ENA
Project description:Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged Acute Lymphoblastic Leukemia’ [RNA-seq]
| PRJNA962586 | ENA
Project description:Pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) exhibit favorable survival rates. However, for AML and ALL patients carrying KMT2A gene translocations clinical outcome remains unsatisfactory. Key players in KMT2A-fusion-driven leukemogenesis include menin and DOT1L. Recently, menin inhibitors like revumenib have garnered attention for their potential therapeutic efficacy in treating KMT2A-rearranged acute leukemias. However, resistance to menin inhibition poses challenges, and identifying which patients would benefit from revumenib treatment is crucial. Here, we investigated the in vitro response to revumenib in KMT2A-rearranged ALL and AML. While ALL samples show rapid, dose-dependent induction of leukemic cell death, AML responses are much slower and promote myeloid differentiation. Furthermore, we reveal that acquired resistance to revumenib in KMT2A-rearranged ALL cells can occur either through the acquisition of MEN1 mutations or independently of mutations in MEN1. Finally, we demonstrate significant synergy between revumenib and the DOT1L inhibitor pinometostat in KMT2A-rearranged ALL, suggesting that such drug combinations represent a potent therapeutic strategy for these patients. Collectively, our findings underscore the complexity of resistance mechanisms and advocate for precise patient stratification to optimize the use of menin inhibitors in KMT2A-rearranged acute leukemia.
| S-EPMC11173273 | biostudies-literature
Project description:BackgroundInfants with KMT2A-rearranged B-cell precursor acute lymphoblastic leukemia (ALL) have poor outcomes. There is an urgent need to identify novel agents to improve survival. Proteasome inhibition has emerged as a promising therapeutic strategy for several hematological malignancies. The aim of this study was to determine the preclinical efficacy of the selective proteasome inhibitor carfilzomib, for infants with KMT2A-rearranged ALL.MethodsEight infant ALL cell lines were extensively characterized for immunophenotypic and cytogenetic features. In vitro cytotoxicity to carfilzomib was assessed using a modified Alamar Blue assay with cells in logarithmic growth. The Bliss Independence model was applied to determine synergy between carfilzomib and the nine conventional chemotherapeutic agents used to treat infants with ALL. Established xenograft models were used to identify the maximal tolerated dose of carfilzomib and determine in vivo efficacy.ResultsCarfilzomib demonstrated low IC50 concentrations within the nanomolar range (6.0-15.8 nm) across the panel of cell lines. Combination drug testing indicated in vitro synergy between carfilzomib and several conventional chemotherapeutic agents including vincristine, daunorubicin, dexamethasone, L-asparaginase, and 4-hydroperoxycyclophosphamide. In vivo assessment did not lead to a survival advantage for either carfilzomib monotherapy, when used to treat both low or high disease burden, or for carfilzomib in combination with multi-agent induction chemotherapy comprising of vincristine, dexamethasone, and L-asparaginase.ConclusionsOur study highlights that in vitro efficacy does not necessarily translate to benefit in vivo and emphasizes the importance of in vivo validation prior to suggesting an agent for clinical use. Whilst proteasome inhibitors have an important role to play in several hematological malignancies, our findings guard against prioritization of carfilzomib for treatment of KMT2A-rearranged infant ALL in the clinical setting.
| S-EPMC8082024 | biostudies-literature