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.

Bone marrow-specific loss of ABI1 induces myeloproliferative neoplasm with features resembling, human myelofibrosis / Chorzalska, Anna; Morgan, John; Ahsan, Nagib; Treaba, Diana O.; Olszewski, Adam J.; Petersen, Max; Kingston, Nathan; Cheng, Yan; Lombardo, Kara; Schorl, Christoph; Yu, Xiaoqing; Zini, Roberta; Pacilli, Annalisa; Tepper, Alexander; Coburn, Jillian; Hryniewicz-Jankowska, Anita; Zhao, Ting C.; Oancea, Elena; Reagan, John L.; Liang, Olin; Kotula, Leszek; Quesenberry, Peter J.; Gruppuso, Philip A.; Manfredini, Rossella; Vannucchi, Alessandro Maria; Dubielecka, Patrycja M.. - In: BLOOD. - ISSN 0006-4971. - 132:19(2018), pp. 2053-2066. [10.1182/blood-2018-05-848408]

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

Zini, Roberta
Investigation
;
Manfredini, Rossella
Writing – Review & Editing
;
2018

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 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.
2018
13-set-2018
132
19
2053
2066
Bone marrow-specific loss of ABI1 induces myeloproliferative neoplasm with features resembling, human myelofibrosis / Chorzalska, Anna; Morgan, John; Ahsan, Nagib; Treaba, Diana O.; Olszewski, Adam J.; Petersen, Max; Kingston, Nathan; Cheng, Yan; Lombardo, Kara; Schorl, Christoph; Yu, Xiaoqing; Zini, Roberta; Pacilli, Annalisa; Tepper, Alexander; Coburn, Jillian; Hryniewicz-Jankowska, Anita; Zhao, Ting C.; Oancea, Elena; Reagan, John L.; Liang, Olin; Kotula, Leszek; Quesenberry, Peter J.; Gruppuso, Philip A.; Manfredini, Rossella; Vannucchi, Alessandro Maria; Dubielecka, Patrycja M.. - In: BLOOD. - ISSN 0006-4971. - 132:19(2018), pp. 2053-2066. [10.1182/blood-2018-05-848408]
Chorzalska, Anna; Morgan, John; Ahsan, Nagib; Treaba, Diana O.; Olszewski, Adam J.; Petersen, Max; Kingston, Nathan; Cheng, Yan; Lombardo, Kara; Schorl, Christoph; Yu, Xiaoqing; Zini, Roberta; Pacilli, Annalisa; Tepper, Alexander; Coburn, Jillian; Hryniewicz-Jankowska, Anita; Zhao, Ting C.; Oancea, Elena; Reagan, John L.; Liang, Olin; Kotula, Leszek; Quesenberry, Peter J.; Gruppuso, Philip A.; Manfredini, Rossella; Vannucchi, Alessandro Maria; Dubielecka, Patrycja M.
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