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

Chorzalska et al., Blood, 2018 asked what drives primary myelofibrosis when the JAK-STAT pathway is not the whole story, since JAK inhibitors relieve symptoms without clearing the disease at the stem cell level. The authors deleted Abi1, which encodes the Abelson interactor 1 adapter protein, in mouse bone marrow. That alone produced a myeloproliferative phenotype with myeloid hyperplasia, megakaryocytosis, progressive marrow fibrosis and splenomegaly, resembling human primary myelofibrosis, together with impaired stem cell self-renewal and hyperactive Src family kinase, STAT3 and nuclear factor kappa B signalling. Cells from patients matched the mouse: Abi-1 protein was down 80% in CD34 positive cells and 50% in CD34 negative cells from people with the disease.

The mouse deletion was conditional and bone marrow specific. To test whether losing ABI1 drives the cell cycle in human cells directly, the authors turned to AUMsilence sdASOs. Human CD34 positive stem and progenitor cells from the bone marrow of three healthy donors were expanded for 48 hours in cytokines, then given the ABI1 oligonucleotides at 15 μM for a further 48 hours, against a scrambled control. The authors state that no transfection reagents were required, since the oligonucleotides self-deliver to primary cells, and they confirmed uptake by confocal microscopy and cell sorting.

Silencing reached more than 50%, and the consequence was immediate: the fraction of CD34 positive cells in S phase nearly doubled. That single experiment carried the argument from a conditional deletion in mouse bone marrow to primary human cells, and the authors read it, with the transplant and cell cycle work in mice, as evidence that losing Abi-1 drives abnormal cell cycle activity and impairs stem cell self-renewal. They went on to show that losing one copy of Abi-1 accelerates disease in an MPL W515L driven mouse model of myeloproliferative neoplasm.