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ABSTRACT: ASXL2 is recurrently mutated in t(8 21) AML and regulates hematopoietic development

PROVIDER: PRJNA416221 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6233520_1.fastq.gz	Fastqsanger.gz
	SRR6233520_2.fastq.gz	Fastqsanger.gz
	SRR6233530_1.fastq.gz	Fastqsanger.gz
	SRR6233530_2.fastq.gz	Fastqsanger.gz
	SRR6233540_1.fastq.gz	Fastqsanger.gz

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ASXL2 is recurrently mutated in t(8 21) AML and regulates hematopoietic development

Project description:ASXL2 is recurrently mutated in t(8 21) AML and regulates hematopoietic development

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ASXL2 is recurrently mutated in t(8 21) AML and regulates hematopoietic development [RNA_Seq_Asxl2_knockout]

Project description:ASXL2 is recurrently mutated in t(8 21) AML and regulates hematopoietic development [RNA_Seq_Asxl2_knockout]

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ASXL2 is recurrently mutated in t(8 21) AML and regulates hematopoietic development [RNA_Seq_Asxl2_mutant]

Project description:ASXL2 is recurrently mutated in t(8 21) AML and regulates hematopoietic development [RNA_Seq_Asxl2_mutant]

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ASXL2 is recurrently mutated in t(8;21) AML and regulates hematopoietic development [RNA_Seq_Asxl2_knockout]

Project description:Chromosomal translocation t(8;21) (q22;q22) leading to generation of oncogenic RUNX1-RUNX1T1 (AML1-ETO) fusion is a cytogenetic abnormality observed in about 10% of acute myelogenous leukemia (AML). To uncover somatic mutations that cooperate with t(8;21)-driven leukemia, we performed targeted and whole exome sequencing of newly-diagnosed and relapsed AML samples. We identified high frequency of truncating alterations in ASXL2 along with recurrent mutations of KIT, TET2, MGA, FLT3, and DHX15 in this subtype of AML. To investigate in-depth the role of ASXL2 in normal and malignant hematopoiesis, we utilized a mouse model of ASXL2 deficiency. Loss of ASXL2 caused progressive hematopoietic defects characterized by myeloid cell expansion, splenomegaly, extramedullary hematopoiesis and poor reconstitution ability in transplantation models. A parallel analysis of young and >1-year old Asxl2-deficient mice revealed age-dependent changes in the hematopoietic compartment leading to perturbations affecting not only myeloid and erythroid differentiation but also maturation of lymphoid cells. Our studies also suggest that expression of truncated ASXL2 protein confers proliferative advantage to mouse myeloid progenitors. Overall, these findings establish a critical role of ASXL2 in maintaining steady state hematopoiesis and provide insights into how its loss/mutation primes leukemic growth of myeloid cells.

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Pervasive Roles of Ubiquitination in Orchestrating the Deubiquitinase Activity and Function of the BAP1/ASXL2 Tumor Suppressor Complex

Project description:The tumor suppressor and deubiquitinase (DUB) BAP1 regulates chromatin-associated processes and is frequently mutated in various malignancies. BAP1 and its drosophila orthologue Calypso assemble DUB complexes with ASXL-1, -2, -3 paralogues and ASX respectively, and these cofactors are required for stimulating their DUB activity. However how the DUB activity of BAP1 is regulated remains largely unknown. Here we show that BAP1 promotes monoubiquitination of ASXLs on the ASXM/DEUBAD domain. ASXL2 monoubiquitination promotes its stability or proteasomal degradation, stimulates BAP1 DUB activity and is required for mammalian cell proliferation. Monoubiquitination of ASXL2 is directly catalyzed by UBE2E family of ubiquitin conjugating enzymes and is regulated by deubiquitination. Monoubiquitination of ASX is regulated by Calypso and is required for drosophila development. We further revealed a switch mechanism that tightly regulate BAP1 function, as a monoubiquitination of BAP1 UCH domain is mutually exclusive with ASXL2 monoubiquitination, thus ensuring highly coordinated DUB-mediated signaling.

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