Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies

H Yang, S Kurtenbach, Y Guo, I Lohse… - Blood, The Journal …, 2018 - ashpublications.org
H Yang, S Kurtenbach, Y Guo, I Lohse, MA Durante, J Li, Z Li, H Al-Ali, L Li, Z Chen…
Blood, The Journal of the American Society of Hematology, 2018ashpublications.org
Abstract Additional Sex Combs-Like 1 (ASXL1) is mutated at a high frequency in all forms of
myeloid malignancies associated with poor prognosis. We generated a Vav1 promoter-
driven Flag-Asxl1 Y588X transgenic mouse model, Asxl1 Y588X Tg, to express a truncated
FLAG-ASXL1aa1-587 protein in the hematopoietic system. The Asxl1 Y588X Tg mice had
an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a
spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid …
Abstract
Additional Sex Combs-Like 1 (ASXL1) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a Vav1 promoter-driven Flag-Asxl1Y588X transgenic mouse model, Asxl1Y588XTg, to express a truncated FLAG-ASXL1aa1-587 protein in the hematopoietic system. The Asxl1Y588XTg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with ASXL1 mutations. ATAC- and RNA-sequencing analyses revealed that the ASXL1aa1-587 truncating protein expression results in more open chromatin in cKit+ cells compared with wild-type cells, accompanied by dysregulated expression of genes critical for HSC self-renewal and differentiation. Liquid chromatography–tandem mass spectrometry and coimmunoprecipitation experiments showed that ASXL1aa1-587 acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Asxl1Y588XTg bone marrow cells to BET bromodomain inhibitors. This study demonstrates that ASXL1aa1-587 plays a gain-of-function role in promoting myeloid malignancies. Our model provides a powerful platform to test therapeutic approaches of targeting the ASXL1 truncation mutations in myeloid malignancies.
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