| First Author | Chorzalska A | Year | 2018 |
| Journal | Blood | Volume | 132 |
| Issue | 19 | Pages | 2053-2066 |
| PubMed ID | 30213875 | Mgi Jnum | J:269936 |
| Mgi Id | MGI:6273064 | Doi | 10.1182/blood-2018-05-848408 |
| Citation | Chorzalska A, et al. (2018) Bone marrow-specific loss of ABI1 induces myeloproliferative neoplasm with features resembling human myelofibrosis. Blood 132(19):2053-2066 |
| abstractText | 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-kappaB 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-kappaB. In aggregate, our data link the loss of Abi-1 function to hyperactive SFKs/STAT3/NF-kappaB signaling and suggest that this signaling axis may represent a regulatory module involved in the molecular pathophysiology of PMF. |
