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

Anna Chorzalska, John Morgan, Nagib Ahsan, Diana O. Treaba, Adam J. Olszewski, Max Petersen, Nathan Kingston, Yan Cheng, Kara Lombardo, Christoph Schorl, Xiaoqing Yu, Roberta Zini, Annalisa Pacilli, Alexander Tepper, Jillian Coburn, Anita Hryniewicz-Jankowska, Ting C. Zhao, Elena Oancea, John L. Reagan, Olin LiangLeszek Kotula, Peter J. Quesenberry, Philip A. Gruppuso, Rossella Manfredini, Alessandro Maria Vannucchi, Patrycja M. Dubielecka

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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 MPNlike 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.

Original languageEnglish
Pages (from-to)2053-2066
Number of pages14
Issue number19
StatePublished - 8 Nov 2018
Externally publishedYes


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