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Bone marrow-specific loss of ABI1 induces myeloproliferative neoplasm with features resembling, human myelofibrosis
- Publication Year :
- 2018
-
Abstract
- Although the pathogenesis of primary myelofibrosis (PMF) and other myeloproliferative neoplasms (MPNs) is linked to constitutive activation of the JAK-STAT pathway, JAK inhibitors have neither curative nor MPN-stem cell-eradicating potential, indicating that other targetable mechanisms are contributing to the pathophysiology of MPNs. We previously demonstrated that Abelson interactor 1 (Abi-1), a negative regulator of Abelson kinase 1, functions as a tumor suppressor. Here we present data showing that bone marrow-specific deletion of Abi1 in a novel mouse model leads to development of an MPN-like phenotype resembling human PMF. Abi1 loss resulted in a significant increase in the activity of the Src family kinases (SFKs), STAT3, and NF-κB signaling. We also observed impairment of hematopoietic stem cell self-renewal and fitness, as evidenced in noncompetitive and competitive bone marrow transplant experiments. CD34+ hematopoietic progenitors and granulocytes from patients with PMF showed decreased levels of ABI1 transcript as well as increased activity of SFKs, STAT3, and NF-κB. In aggregate, our data link the loss of Abi-1 function to hyperactive SFKs/STAT3/NF-κB signaling and suggest that this signaling axis may represent a regulatory module involved in the molecular pathophysiology of PMF.
- Subjects :
- 0301 basic medicine
Biochemistry
Immunology
Hematology
Cell Biology
CD34
Hematopoietic stem cell
Biology
medicine.disease
ABI1
03 medical and health sciences
Haematopoiesis
030104 developmental biology
medicine.anatomical_structure
medicine
Cancer research
Bone marrow
Signal transduction
Myelofibrosis
Myeloproliferative neoplasm
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....4408f3c04d0a5484b426e1648faeb3bf