HDAC7 is a major contributor in the pathogenesis of t(4;11)/MLL-AF4+ infant B-cell acute lymphoblastic leukemia
Infants diagnosed of precursor B-cell acute lymphoblastic leukemia (iB-ALL) presenting MLL-AF4 chromosomal rearrangement are at high risk of disease progression into fatal outcome. This specific subtype of pediatric leukemia constitutes a tough challenge in leukemia research, given the difficulties found when trying in vivo modelling. However, the understanding of mechanisms leading to proper lymphocyte generation may become of high utility in gaining deep insight on this malignancy. As we report here, the lack of HDAC7, a key transcriptional regulator in B lymphocyte differentiation, worsens the prognosis of iB-ALL patients. In fact, MLL-AF4+ iB-ALL patients with high expression of HDAC7 display an improved survival, partially mediated by the repression of oncogenes, such as c-MYC, and chemoresistance markers, like the ASNS enzyme. Accordingly, HDAC7 drastically reduces leukemic cells proliferation in MLL-AF4+ iB-ALL through the induction of apoptosis. Moreover, RNA sequencing of HDAC7-overexpressing cells has revealed that HDAC7 alters the genomic profiling of MLL-AF4+ iB-ALL cells towards that of healthy B-cell progenitors. In summary, the findings here reported highlight the role of HDAC7 in predicting prognosis of a lethal subtype of iB-ALL and open new clinical perspectives, since MLL-AF4+ iB-ALL infants would highly benefit from therapeutic options eventually restoring HDAC7 expression. Overall design: SEM-K2 cells (derived from an infant diagnosed of MLL-AF4+ iB-ALL) were transduced with a Tet-On-Tight system, either containing HDAC7 transcription factor or its corresponding empty vector, in order to conditionally overexpress HDAC7. RNA was extracted from SEM-TetOn-Tight-control and SEM-TetOn-Tight-HDAC7 cells. In both cases, both samples treated with doxycycline and untreated ones were obtained. For RNAseq analysis, three replicates for condition were processed. The unspecific effect of doxycycline was removed from that of HDAC7 by removing the DEGs between SEM-TetOn-Tight control + Doxycycline and untreated control cells.