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

Abstract

<jats:title>Abstract</jats:title> <jats:p>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 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.</jats:p>

Dual Mechanisms of Action of Self-Delivering, Anti-HIV-1 FANA Oligonucleotides as a Potential New Approach to HIV Therapy

“…It has been reported that intracellular delivery of FANA ASOs in multiple cell lines, including CD34 + stem cells, can be accomplished in the absence of delivery agents such as carrier vehicles or molecular conjugations 19, 20. Therefore, we first determined whether FANA ASOs could be internalized into PBMCs without the help of delivery agents.…”

“…: 19 they showed that PS-modified FANA ASOs are compatible with gymnotic delivery in multiple cell lines and are as effective at inhibiting gene expression as corresponding LNA-modified ASOs. More recently, Chorzalska et al 20 . demonstrated that FANA ASOs gymnotically silenced a target gene (Abi-1) with knockdown efficiency greater than 50% in human CD34 + cells isolated from the bone marrow of healthy donors.…”

Myelofibrosis biology and contemporary management

“…In murine models, loss of Abi-1 induces features similar to myelofibrosis by activation of Src family kinases, STAT3 and NF-kB, suggesting a means for myelofibrosis that is beyond JAK2 activation. 58…”

Murine Models of Myelofibrosis

“…Reduced ABI-1 gene expression was observed in granulocytes from PMF patients and patients with MF secondary to PV but not in ET, PV, or MF secondary to ET. Hence, Chorzalska et al induced conditional deletion of Abi-1 in mice using the Mx1Cre system [ 63 ] ( Table 2 ). Loss of Abi-1 in the bone marrow of mice resulted in a PMF phenotype featuring leukocytosis, thrombocytosis, anemia, splenomegaly, megakaryocytosis, and fibrosis in the bone marrow.…”