Transcriptional control of CBX5 by the RNA-binding proteins RBMX and RBMXL1 maintains chromatin state in myeloid leukemia

Kharas and colleagues identify the RNA-binding proteins RBMX and RBMXL1 as AML tumor promoters that alter chromatin compaction and hence cell survival via transcriptional regulation of the heterochromatin protein encoded by CBX5. RNA-binding proteins (RBPs) are key arbiters of post-transcriptional regulation and are found to be dysregulated in hematological malignancies. Here we identify the RBP RNA-binding motif protein, X-linked (RBMX; also known as hnRNPG), and its retrogene RBMXL1 to be required for murine and human myeloid leukemogenesis. RBMX and RBMXL1 were overexpressed in individuals with acute myeloid leukemia (AML) compared to healthy individuals, and RBMX/RBMXL1 loss delayed leukemia development. RBMX/RBMXL1 loss lead to global changes in chromatin accessibility as well as chromosomal breaks and gaps. We found that RBMX and RBMXL1 directly bind to mRNAs, affect transcription of multiple loci, including CBX5 (also known as heterochromatin protein 1 alpha (HP1-alpha)), and control the nascent transcription of the CBX5 locus. Forced CBX5 expression rescued the RBMX/RBMXL1 depletion effects on cell growth and apoptosis. Overall, we determined that RBMX and RBMXL1 control leukemia cell survival by regulating chromatin state through the downstream target CBX5. These findings identify a mechanism for RBPs directly promoting transcription and suggest RBMX and RBMXL1, as well as CBX5, as potential therapeutic targets in myeloid malignancies.