De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA417713 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6276850_1.fastq.gz | Fastqsanger.gz | |||
| SRR6276850_2.fastq.gz | Fastqsanger.gz | |||
| SRR6276860_1.fastq.gz | Fastqsanger.gz | |||
| SRR6276860_2.fastq.gz | Fastqsanger.gz | |||
| SRR6276870_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 100 |
Similar Datasets
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: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 FLT3 ITD , FLT3 N676K , and NRAS G12D accelerate KMT2A-MLLT3 leukemia onset. Further, also subclonal FLT3 N676K mutations accelerate disease, possibly by providing stimulatory factors. Herein, we show that one such factor, MIF, promotes survival of mouse KMT2A-MLLT3 leukemia initiating cells. We identify acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 in KMT2A-MLLT3 leukemia cells that favored clonal expansion. During clonal evolution, we observe serial genetic changes at the Kras G12D locus, consistent with a strong selective advantage of additional Kras G12D . KMT2A-MLLT3 leukemias with signaling mutations enforce Myc and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlight the importance of activated signaling as a contributing driver.
| S-EPMC5932012 | biostudies-literature
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: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.
2023-03-11 | PXD036669 | Pride
Project description:The histone methyltransferases DOT1L (H3K79me1,2,3 KMT, "activating" chromatin mark) and EZH2 (H3K27me1,2,3 KMT, "silencing" mark) have both been shown to be required for growth and survival of KMT2A rearranged AML cells. Both KMTs have been shown to modulate expression of HOXA cluster genes, albeit for EZH2 this has not been shown in the context of KMT2A rearranged AML, but in other subtypes of AML. We asked what transcriptional effects dual inhibition of DOT1L and EZH2 has in KMT2A rearranged AML.
2019-07-17 | GSE134369 | GEO
Project description:The histone methyltransferases DOT1L (H3K79me1,2,3 KMT, "activating" chromatin mark) and EZH2 (H3K27me1,2,3 KMT, "silencing" mark) have both been shown to be required for growth and survival of KMT2A rearranged AML cells. Both KMTs have been shown to modulate expression of HOXA cluster genes, albeit for EZH2 this has not been shown in the context of KMT2A rearranged AML, but in other subtypes of AML. We asked what transcriptional effects dual inhibition of DOT1L and EZH2 has in KMT2A rearranged AML.
2020-04-29 | GSE149520 | GEO
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.
2023-03-11 | PXD032980 | 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: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.
2023-03-30 | GSE201137 | GEO
Project description:The KMT2A rearranged B lineage infant ALL cell line SEM was treated with the proteasome inhibitor bortezomib followed by a multiplexed mass spectrometry-based proteomic analysis at multiple time points (0, 6, 12, 16, and 20 hours) over 20 hours to further understand the cellular response of these cells to proteasome inhibition.
2023-02-15 | PXD038845 | Pride