Journal
BLOOD
Volume 132, Issue 19, Pages 2053-2066Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2018-05-848408
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Funding
- Brown Biomed Division Dean's Award
- University of Medicine Foundation Integration
- Rhode Island Foundation
- Lifespan Center of Biomedical Research Excellence for Cancer Research Development (National Institutes of Health/National Institute of General Medical Sciences) [1P30GM110759, 1P20GM119943]
- Savit Foundation
- Associazione Italiana per la Ricerca sul Cancro (AIRC, Milan, Italy)
- Special Program Molecular Clinical Oncology 5x1000 [1005]
- National Institutes of Health/National Cancer Institute [R01CA161018]
- American Society of Hematology Research Scholar award
- NATIONAL CANCER INSTITUTE [R01CA161018] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL066987] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [U54GM115677, T32GM077995, P20GM119943, P30GM110759] Funding Source: NIH RePORTER
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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 Abil in a novel mouse model leads to development of an MPN-like phenotype resembling human PMF. Abi-1 loss resulted in a significant increase in the activity of the Src family kinases (SFKs), STAT3, and NF-kappa B 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 ABIl transcript as well as increased activity of SFKs, STAT3, and NF-kappa B. In aggregate, our data link the loss of Abi-1 function to hyperactive SFKs/ST/NF-kappa B signaling and suggest that this signaling axis may represent a regulatory module involved in the molecular pathophysiology of PMF.
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