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The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia

ABSTRACT: The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia

PROVIDER: PRJNA1015615 | ENA |

REPOSITORIES: ENA

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The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia [RNAseq_MOLM13_HMX3_KD]

Project description:The KMT2A::MLLT3 fusion protein causes acute myeloid leukemia (AML) by activating the oncogenic transcription factor MECOM. However, MECOM expression occurs only in half of the cases. By integrating gene expression and enhancer activity data from patient cells, we identified neuronal homeobox transcription factor HMX3 as cell fate determining factor in MECOM-negative KMT2A::MLLT3 AML. HMX3 expression associated with younger age and KMT2A-rearranged leukemia in large AML cohorts (p<0.002). It was absent in other major genetic risk groups and healthy blood cells. Transcriptomic analyses revealed that HMX3 drives cancer-associated E2F, MYC, and cell cycle gene programs. Ectopic HMX3 expression completely inhibited monocytic but not granulocytic colony formation of healthy CD34+ cord blood cells. Its silencing in KMT2A::MLLT3 AML cell lines and patient cells resulted in cell cycle arrest, monocytic differentiation, and apoptosis. Thus, HMX3 is a leukemia-specific vulnerability that enhances proliferation and blocks differentiation of MECOM-negative KMT2A::MLLT3 leukemia.

2024-12-13 | GSE242962 | GEO

The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia [RNAseq_CD34_HSPC_ectopic_HMX3]

2024-12-13 | GSE242956 | GEO

The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia [RNAseq_primary_HMX3_KMT2A-MLLT3_AML]

2024-12-13 | GSE242961 | GEO

The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia [RNAseq_CD34_HSPC_ectopic_HMX3]

Project description:The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia [RNAseq_CD34_HSPC_ectopic_HMX3]

| PRJNA1015617 | ENA

The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia [RNAseq_MOLM13_HMX3_KD]

Project description:The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia [RNAseq_MOLM13_HMX3_KD]

| PRJNA1015622 | ENA

The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia [RNAseq_primary_HMX3_KMT2A-MLLT3_AML]

Project description:The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia [RNAseq_primary_HMX3_KMT2A-MLLT3_AML]

| PRJNA1015623 | ENA

FLT3-N676K drives acute myeloid leukemia in a xenograft model of KMT2A-MLLT3 leukemogenesis

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

KMT2A-rearranged leukemia proteomics

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

The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-12-13 | GSE242963 | GEO

Enhancer-activated RET confers protection against oxidative stress to KMT2A-rearranged acute myeloid leukemia.

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

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