HDAC inhibitor derivatives induce differentiation of leukemic cells through two distinct and separable mechanisms
Kumar, P.; Josa-Cullere, L.; Jackson, T. R.; Bataille, C. J. R.; Vyas, P.; Milne, T. A.; Russell, A. J.
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Acute myeloid leukaemia (AML) is a haematopoietic malignancy comprising different genetic subtypes with a common hallmark of differentiation arrest. In abnormal haematopoiesis, overcoming the differentiation blockade has emerged as an attractive therapeutic strategy. In a screen with genetically distinct AML cell lines, histone deacetylase inhibitors (HDACis) were observed to cause an upregulation in the expression of CD11b, a myeloid differentiation marker. These caused changes in cell morphology, block in proliferation, and cell cycle arrest at the G1 phase. To gain insights onto the mechanism of these compounds, we planned to prepare inactive probes devoid of the zinc binding motif. However, these compounds were unexpectedly still able to initiate differentiation, albeit through a distinct target and via a G2 arrest. Subsequent RNA sequencing studies supported the differentiation phenotype for the HDACis and highlighted the role of cell cycle regulatory kinases for the effect observed in the probe molecules. We then showed that these inhibit Aurora A and GSK3 kinases, suggesting their potential as therapeutic targets for differentiation therapy in AML. Our work supports the importance of properly validating inactive tool compounds and their potential to identify novel targets.
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