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

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

Crystal structures of (2E)-1-(3-bromo­thio­phen-2-yl)-3-(2-meth­­oxy­phen­yl)prop-2-en-1-one and (2E)-1-(3-bromo­thio­phen-2-yl)-3-(3,4-di­meth­­oxy­phen­yl)prop-2-en-1-one

In the mol­ecules of the title compounds, (2E)-1-(3-bromo-thio­phen-2-yl)-3-(2-meth­oxy­phen­yl)prop-2-en-1-one, C14H11BrO2S, (I), which crystallizes in the space group P-1 with four independent mol­ecules in the asymmetric unit (Z′ = 8), and (2E)-1-(3-bromo­thio­phen-2-yl)-3-(3,4-di­meth­oxy­phen­yl)prop-2-en-1-one, C15H13BrO3S, (II), which crystallizes with Z′ = 8 in the space group I2/a, the non-H atoms are nearly coplanar. The mol­ecules of (I) pack with inversion symmetry stacked diagonally along the a-axis direction. Weak C—H⋯Br intra­molecular inter­actions in each of the four mol­ecules in the asymmetric unit are observed. In (II), weak C—H⋯O, bifurcated three-center inter­molecular inter­actions forming dimers along with weak C—H⋯π and π–π stacking inter­actions are observed, linking the mol­ecules into sheets along [001]. A weak C—H⋯Br intra­molecular inter­action is also present. There are no classical hydrogen bonds present in either structure