FLT3-N676K drives acute myeloid leukemia in a xenograft model of KMT2A-MLLT3 leukemogenesis
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ABSTRACT:
PROVIDER: PRJNA524875 | ENA |
REPOSITORIES: ENA
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Project description:Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements. Herein, we show that co-expression of FLT3-N676K and KMT2A-MLLT3 in human CD34+ cord blood cells primarily cause acute myeloid leukemia (AML) and rarely acute lymphoblastic leukemia (ALL) in immunodeficient mice. By contrast, expression of KMT2A-MLLT3 alone cause ALL, double-positive leukemia (DPL, expressing both CD33 and CD19), or bilineal leukemia (BLL, comprised of distinct myeloid and lymphoid leukemia cells), and rarely AML. Further, AML could only be serially propagated with maintained immunophenotype in secondary recipients when cells co-expressed KMT2A-MLLT3 and FLT3-N676K. Consistent with the idea that activated signaling would allow myeloid cells to engraft and maintain their self-renewal capacity, in a secondary recipient, a de novo KRAS-G13D was identified in myeloid cells previously expressing only KMT2A-MLLT3. Gene expression profiling revealed that KMT2A-MLLT3 DPL had a highly similar gene expression profile to ALL, with both expressing key lymphoid transcription factors and ALL cell surface markers, in line with the DPL cells being ALL cells with aberrant expression of CD33. Taken together, our results highlight the need for constitutive active signaling mutations for driving myeloid leukemia in a human xenograft model of KMT2A-R acute leukemia.
2019-04-05 | GSE127492 | 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:KMT2A-MLLT3, a fusion protein formed by the t(9;11) translocation in acute myeloid leukemia, is an epigenetic transcription factor that is known to regulate a unique leukemic gene expression profile. We show that rearranged during transfection (RET) proto-oncogene is highly overexpressed in the KMT2A-MLLT3 subgroup. In addition to biochemical studies, the RNA-seq and ATAC seq analyses have been performed in KMT2A-MLLT3 positive MOLM-13 AML cell line, compared to the umbilical cord blood-driven CD34+ hematopoietic stem progenitor cells.
2024-03-04 | GSE241867 | GEO
Project description:RNA-seq analysis of murine KMT2A-MLLT3 with DOT1L overexpressed
| PRJNA553528 | ENA
Project description:Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3ITD, FLT3N676K, and NRAS G12D accelerate KMT2A-MLLT3 leukemia onset. Subclonal FLT3N676K mutations also accelerate disease, possibly by providing stimulatory factors such as Mif. Acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 were identified in KMT2A-MLLT3 leukemia cells and favored clonal expansion. During clonal evolution, serial genetic changes at the KrasG12D locus was observed, consistent with a strong selective advantage of additional KrasG12D. KMT2A-MLLT3 leukemias with signaling mutations enforced Myc- and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlights the importance of activated signaling as a contributing driver in this disease.
2018-05-02 | GSE106714 | GEO
Project description:We transduced two individual murine KMT2A-MLLT3 AML samples with DOT1L and three days after sorting for DOT1L+ cells collected for RNA-seq MLL-rearranged leukemias have been previously shown to be dependent on the presence of histone 3 lysine 79 (H3K79) dimethylation on the genomic targets of the fusion, and an inhibitor of the H3K79 methyltransferase DOT1L is in clinical trials for MLL-rearranged leukemia. In order to ask what biologic effects overexpression of DOT1L would have on the H3K79me2 ChIP-Seq profiles and MLL-fusion target gene expression, murine leukemias generated by transplanting MSCV-MLL-AF9-GFP transduced lin- cKit+ Sca1+ bone marrow cells were subjected to overexpression of DOT1L. Cells were sorted into low (low level of DOT1L overexpression), high (high level of DOT1L overexpression) and bulk (entire population) samples, and subjected to H3K79me2 ChIP-Seq (using a drosophila spike in for normalization) and RNA-Seq analysis 3 days after transduction.
2019-07-10 | GSE134035 | GEO
Project description:We have developed a human model leukemia system where healthy cord blood (CB) cells from single donors are used to generate dozens of human leukemias driven by KMT2A fusions. These models have been used for the study of the stepwise changes in donor CB cells as they undergo leukemic transformation driven by the KMT2A-MLLT3 (KM3) fusion gene. We specifically studied the epigenetic changes that occur in this specific AML subgroup through ChIP-seq of histone modifications and ATAC-seq and DNA methylation through Methyl-Seq.
2020-07-01 | GSE142579 | GEO
Project description:MLL-fusion-mediated activation of FLT3-ITD lesions promotes leukemogenesis
| PRJNA681873 | ENA
Project description:MLL-rearranged (MLL-r) leukemia, a particularly intractable disease, depends on DOT1L-mediated H3K79 methylation. Depletion of this transcriptionally activating mark by DOT1L loss-of-function or high concentrations of highly-specific inhibitor pinometostat (≥1 mM EPZ5676) leads to the downregulation of HOXA9 and MEIS1, and consequent reduction leukemia survival. . Yet, some MLL-r cell lines are inexplicably susceptible to low-dose pinometostat, below the threshold for downregulating these canonical oncogenic drivers. Here we define alternative pathways disrupted by low-dose pinometostat (10 nM), a concentration that reduces proliferation of the MLL-r MV4;11 cell line without affecting HOXA9 and MEIS1 expression and downregulates a subset of MLL-fusion targets including FLT3, one of the most commonly mutated genes in leukemia. Using quantitative ICeChIP-seq, we observe profound H3K79me2 depletion at downregulated MLL-r targets, with resulting increases in transcriptionally activating H3K4me3 at promoters and reductions in repressive H3K27me3. The presence of co-occurring activating FLT3 mutations, portend greater cytotoxicity to inhibitor treatment. Although downregulation of polycomb components modestly contributes to reductions in proliferation, overexpression of constitutively active STAT5A, a target of FLT3-ITD-signalling, nearly completely rescues proliferation, accounting for the bulk of cytotoxicity from H3K79me2 depletion. We also observe a dependence of FLT3-STAT5A signaling on MLL function, suggesting that the FLT3 locus is exquisitely sensitivity to both H3K79me2 and H3K4me3 depletion and arguing that combinations of DOT1L, MLL1 and FLT3 inhibitors should be explored for treating the ~30% of all leukemias that carry FLT3 mutations.
2021-07-15 | GSE162441 | GEO
Project description:we observed synergistic cytotoxic effects, preferentially reducing cell proliferation and inducing apoptosis in FLT3/ITD+ AML cell lines and in primary AML cells. Furthermore, the combination of FLT3-TKI and GSI eradicated leukemic cells and prolonged survival in a FLT3/ITD+ patient derived xenograft (PDX) AML model. Mechanistically, decreased expression of CXCR3 that lead to down-regulated ERK signaling was partially responsible for the observed synergy. Our findings suggest that combined therapies of FLT3-TKIs with GSI may be exploited as a potential therapeutic strategy to treat FLT3/ITD+ AML.
2019-02-23 | GSE126933 | GEO