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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE106798 | GEO | 2018/12/01

REPOSITORIES: GEO

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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.

2018-12-01 | GSE106797 | GEO

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

2018-12-01 | GSE106796 | GEO

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

| PRJNA418083 | ENA

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]

| PRJNA418089 | ENA

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]

| PRJNA418090 | ENA

The RUNX1-ETO target gene RASSF2 suppresses t(8;21) AML development and regulates Rac GTPase signaling.

Project description:Large-scale chromosomal translocations are frequent oncogenic drivers in acute myeloid leukemia (AML). These translocations often occur in critical transcriptional/epigenetic regulators and contribute to malignant cell growth through alteration of normal gene expression. Despite this knowledge, the specific gene expression alterations that contribute to the development of leukemia remain incompletely understood. Here, through characterization of transcriptional regulation by the RUNX1-ETO fusion protein, we have identified Ras-association domain family member 2 (RASSF2) as a critical gene that is aberrantly transcriptionally repressed in t(8;21)-associated AML. Re-expression of RASSF2 specifically inhibits t(8;21) AML development in multiple models. Through biochemical and functional studies, we demonstrate RASSF2-mediated functions to be dependent on interaction with Hippo kinases, MST1 and MST2, but independent of canonical Hippo pathway signaling. Using proximity-based biotin labeling we define the RASSF2-proximal proteome in leukemia cells and reveal association with Rac GTPase-related proteins, including an interaction with the guanine nucleotide exchange factor, DOCK2. Importantly, RASSF2 knockdown impairs Rac GTPase activation, and RASSF2 expression is broadly correlated with Rac-mediated signal transduction in AML patients. Together, these data reveal a previously unappreciated mechanistic link between RASSF2, Hippo kinases, and Rac activity with potentially broad functional consequences in leukemia.

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Addiction of t(8;21) and inv(16) AML to native RUNX1

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-08-17 | E-GEOD-45748 | biostudies-arrayexpress

Hematopoietic differentiation at single-cell resolution in NPM1-mutated AML.

Project description: Not available

| S-EPMC9508105 | biostudies-literature

Addiction of t(8;21) and inv(16) AML to native RUNX1

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

2013-08-17 | GSE45748 | GEO

ALKBH5 regulates AML development and LSC as an m6A eraser

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