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 Liang, Leszek Kotula, Peter J. Quesenberry, Philip A. Gruppuso, Rossella Manfredini, Alessandro Maria Vannucchi and Patrycja M. Dubielecka

Key points

  • Bone marrow-specific deletion of Abi1 in mice results in MPN-like phenotype and is linked to hyperactive SFKs/STAT3/NF-κB signaling.

  • ABI1 is downregulated in hematopoietic stem/progenitor cells and granulocytes from patients with PMF.


Although the pathogenesis of primary myelofibrosis (PMF) and other myeloproliferative neoplasms (MPNs) is linked to constitutive activation of the JAK-STAT pathway, JAK inhibitors neither have curative nor MPN-stem cell-eradicating potential, indicating that other targetable mechanisms are contributing to 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 cells self-renewal and fitness, as evidenced in non-competitive 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.

  • Submitted May 2, 2018.
  • Accepted September 1, 2018.