Abstract
AbstractAlthough 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-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.
Highlights
IntroductionThe phenotype of primary myelofibrosis (PMF) is characterized by progressive bone marrow fibrosis, organomegaly, extramedullary hematopoiesis, thromboembolism, and marrow failure or transformation to acute myeloid leukemia (AML).[1,2,3] Median survival in PMF varies between 1 and 15 years, depending on risk factors, and treatment options are limited.[3,4] Identification of JAK2-activating mutations as major drivers in myeloproliferative neoplasms (MPNs) prompted clinical development of JAK2 inhibitors.[5,6] Ruxolitinib, an ATP-mimetic JAK1/2 inhibitor, induces symptomatic improvement in PMF, but exacerbates associated cytopenias and does not have curative potential, and responses occur regardless of presence of JAK2 mutations.[7,8,9,10,11] a major need remains to identify other targetable mechanisms contributing to the pathogenesis of PMF and related MPNs, polycythemia vera (PV), and essential thrombocythemia (ET).Abelson Interactor 1 (Abi-1) is a negative regulator of Abl[1] kinase,[12,13,14,15] involved in regulation of cell proliferation.[16,17] By forming a complex with Wiskott-Aldrich syndrome protein family member 2 (WAVE2),[18,19] Wiskott-Aldrich Syndrome protein (WASP), or Diaphanous (Dia) formin,[16,18,19,20,21,22,23] Abi-1 affects actin remodeling, cell adhesion, and migration
We found that conditional deletion of Abi[1] in murine bone marrow results in impairment of hematopoietic stem cell self-renewal, progressive anemia, megakaryocytosis and myeloid hyperplasia, with resulting primary myelofibrosis (PMF)-like phenotype characterized by marrow fibrosis and splenomegaly
Gene expression profiles (GEO/ GSE53482)[42] of CD341 cells isolated from peripheral blood (PB) showed significant downregulation of ABI1 in PMF (n 5 42) with mutations in JAK2 or CALR relative to controls (n 5 31; supplemental Figure 1A-C)
Summary
The phenotype of primary myelofibrosis (PMF) is characterized by progressive bone marrow fibrosis, organomegaly, extramedullary hematopoiesis, thromboembolism, and marrow failure or transformation to acute myeloid leukemia (AML).[1,2,3] Median survival in PMF varies between 1 and 15 years, depending on risk factors, and treatment options are limited.[3,4] Identification of JAK2-activating mutations as major drivers in myeloproliferative neoplasms (MPNs) prompted clinical development of JAK2 inhibitors.[5,6] Ruxolitinib, an ATP-mimetic JAK1/2 inhibitor, induces symptomatic improvement in PMF, but exacerbates associated cytopenias and does not have curative potential, and responses occur regardless of presence of JAK2 mutations.[7,8,9,10,11] a major need remains to identify other targetable mechanisms contributing to the pathogenesis of PMF and related MPNs, polycythemia vera (PV), and essential thrombocythemia (ET).Abelson Interactor 1 (Abi-1) is a negative regulator of Abl[1] kinase,[12,13,14,15] involved in regulation of cell proliferation.[16,17] By forming a complex with Wiskott-Aldrich syndrome protein family member 2 (WAVE2),[18,19] Wiskott-Aldrich Syndrome protein (WASP), or Diaphanous (Dia) formin,[16,18,19,20,21,22,23] Abi-1 affects actin remodeling, cell adhesion, and migration. Abi-1 interacts with integrin a4 and is involved in integrin b1 signaling.[24,25,26]
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