Epigenetic drug library screening identified an LSD1 inhibitor to target UTX-deficient cells for differentiation therapy

Abstract

UTX (also known as KDM6A), a histone 3 lysine 27 demethylase, is among the most frequently mutated epigenetic regulators in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Recent studies have suggested that UTX mutations promote MDS and AML by blocking the differentiation of hematopoietic stem and progenitor cells (HSPCs). Here, we performed an epigenetic drug library screening for small molecules able to release the differentiation block on HSPCs induced by UTX deficiency. We found that SP2509, a selective inhibitor of LSD1, specifically promoted the differentiation of Utx -null HSPCs while sparing wild-type HSPCs. Transcriptome profiling showed that Utx loss reduced the expression of differentiation-related and tumor suppressor genes, correlating with their potential roles in HSPC self-renewal and leukemogenesis. In contrast, SP2509 treatment reversed these changes in gene expression in Utx -null HSPCs. Accordingly, Utx loss decreased H3K4 methylation level probably through the COMPASS-like complex, while LSD1 inhibition by SP2509 partially reversed the reduction of H3K4 methylation in Utx -deficient HSPCs. Further, SP2509 promoted the differentiation of Utx -null AML cells in vitro and in vivo and, therefore, extended the survival of these leukemic mice. Thus, our study identified a novel strategy to specifically target both premalignant and malignant cells with Utx deficiency for differentiation therapy and provided insights into the molecular mechanisms underlying the role of Utx in regulating HSPCs and related diseases.

Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury

“…Although ample evidence in various endothelial cell lines has indicated mitochondrial ETC as the main source of I/R-related ROS, there is a possibility of cross-talk between NOX isoforms and mitochondria [66]. Of note, NOX4 is localized along the inner mitochondrial membrane, and the potential interaction between these two sources of ROS may be significant determinants of the total mtROS in the endothelium [67,68].…”

The expanding vulnerabilities of being UTXless

“…In a recent study. 1 published in Signal Transduction and Targeted Therapy, Dr. Yu Liu and collaborators report that the differentiation block in UTX-null leukemia cells can be reverted by an LSD1 inhibitor, highlighting additional ways of targeting UTX-deficient malignancies.…”

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

“…These authors propose a model in which both LSD1 and the malfunctioning COMPASS-like complex demethylate H3K4. LSD1 inhibition increases H3K4 methylation and restores differentiation [ 127 ]. In summary, loss of KDM6A contributes to leukemogenesis and drug resistance in myeloid malignancies both dependent on and independent of its enzymatic activity ( Figure 2 ).…”