دورية
Bone marrow–specific loss of ABI1induces myeloproliferative neoplasm with features resembling human myelofibrosis
| العنوان: | Bone marrow–specific loss of ABI1induces myeloproliferative neoplasm with features resembling human myelofibrosis |
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| المؤلفون: | 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. |
| المصدر: | Blood; November 2018, Vol. 132 Issue: 19 p2053-2066, 14p |
| مستخلص: | 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 Abi1in a novel mouse model leads to development of an MPN-like phenotype resembling human PMF. Abi1loss 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 ABI1transcript 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. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 00064971 15280020 |
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| DOI: | 10.1182/blood-2018-05-848408 |