RNA-seq of murine spleocytes

Aberrant expression of the T-cell lymphoma/leukemia 1A (TCL1A) oncogene is a hallmark of chronic lymphocytic leukemia (CLL) and is associated with aggressive disease features. A better understanding of functional networks around TCL1A is required to develop new treatment approaches in CLL. Here, we identify the epigenetic modifying lysine-specific demethylase KDM1A as a nuclear interaction partner of the TCL1A protein in CLL B-cells. Interestingly, binding to TCL1A increased KDM1A?s demethylase activity. Moreover, higher KDM1A expression correlated with adverse clinical characteristics and shorter progression-free survival in CLL. Kdm1a knockdown (Kdm1a-KD) reduced leukemic burden and prolonged overall survival in a CLL mouse model accompanied by upregulation of p53 and pro-apoptotic pathways. RNA-seq analysis of differentially expressed genes upon Kdm1a-KD suggests that Kdm1a might act as a transcriptional repressor. In addition, ChIP experiments demonstrated an altered modification of H3K4me3 in Kdm1a-KD mice. Moreover, KDM1A expression in the microenvironmental had an impact on its support for CLL progression. In line, KDM1A inhibition by the pharmacologic compound C12 induced apoptosis and affected H3K4/9 target methylation levels in B-cell lines and CLL samples. Overall, we found a relevant pathogenetic role of KDM1A as a pro-oncogenic marker in CLL cells and their microenvironment. This provides a novel treatment rationale for targeting KDM1A in CLL. Overall design: We reported the gene expression changes in CLL mouse model upon KDM1A knockdown. An doxycycline-inducible KDM1A knockdown Eµ-TCL1A mouse model was established. Leukemic mice were treated with doxycycline to induce KDM1A knockdown. RNA-seq of splenic mononuclear cells from KDM1AKD;Eµ-TCL1A and Eµ-TCL1A