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Combined LSD1 and ATRA in AML
nation promotes cytotoxic response provides an addition- al rationale to explore this combination in AML patients. Treatment of non-APL AML cell lines with GSK2879552 and ATRA results in synergistic cleavage of caspases 3 and 7, the executioner caspases.35 The synergistic cell death occurs after the observed changes in cell surface marker expression and may suggest that as cells reach terminal differentiation, this process is a signal to the cells to under- go apoptosis in a manner similar to the life cycle of normal immune cells.36 Given that the gene set enrichment analy- sis revealed that the lysosome and mTOR pathways are also affected with the combination, another possibility is
that the differentiation triggers an autophagic response that leads to a switch to apoptosis.28 Importantly, applying the combination to primary patient samples ex vivo suc- cessfully illustrates that a beneficial combination effect is not restricted to cultured cell lines. The broad response of cell lines and primary AML samples to the combination does preclude the ability to identify a biomarker preclini- cally. Pretreatment biopsy assessment will, therefore, be required to determine which patients will most likely respond to the combination. Taken together, these results highlight the possibility of achieving a cure in AML through treatment with LSD1 inhibitors and ATRA.
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