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Blood. 2018 Nov 8;132(19):2053-2066. doi: 10.1182/blood-2018-05-848408. Epub 2018 Sep 13.

Bone marrow-specific loss of ABI1 induces myeloproliferative neoplasm with features resembling human myelofibrosis.

Author information

1
Signal Transduction Laboratory, Division of Hematology/Oncology at Rhode Island Hospital and Warren Alpert Medical School at Brown University, Providence, RI.
2
Flow Cytometry and Cell Sorting Core Facility, Roger Williams Medical Center, Providence, RI.
3
Center of Biomedical Research Excellence (COBRE), Center for Cancer Research Development, Proteomics Core Facility, Rhode Island Hospital, Providence, RI.
4
Division of Biology and Medicine, Brown University, Providence, RI.
5
Department of Pathology and Laboratory Medicine at Rhode Island Hospital and Warren Alpert Medical School at Brown University, Providence, RI.
6
Division of Hematology/Oncology at Rhode Island Hospital and Warren Alpert Medical School at Brown University, Providence, RI.
7
Genomics Core Facility, Brown University, Providence, RI.
8
Department of Biostatistics, Yale School of Public Health, New Haven, CT.
9
Center for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
10
CRIMM, Center for Research and Innovation for Myeloproliferative Neoplasms, AOU Careggi, and.
11
Department of Experimental and Clinical Medicine, University of Florence, Excellence Center Denothe, Florence, Italy.
12
Cytobiochemistry Laboratory, Department of Biotechnology, University of Wroclaw, Wroclaw, Poland.
13
Department of Urology, State University of New York Upstate Medical University, Syracuse, NY.
14
Cardiovascular Laboratory, Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI.
15
Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI; and.
16
Department of Pediatrics, Brown University and Rhode Island Hospital, Providence, RI.

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.

PMID:
30213875
PMCID:
PMC6236464
DOI:
10.1182/blood-2018-05-848408
[Indexed for MEDLINE]
Free PMC Article

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