Gene expression signature of IKZF1 deleted B-cell acute lymphoblastic leukaemia reveals a unique regulation of MUC4.

Abstract

The IKAROS (IKZF1) transcription factor regulates the differentiation of pre-B cells to mature B lymphocytes. The loss of IKZF1 expression has been linked with increased matrix adhesion along with increased expression of stemness markers that form a hallmark of B-lymphoblasts. However, the spectrum of differentially regulated genes has not been investigated in detail in B-cell acute lymphoblastic leukaemia (B-ALL) patients expressing IKZF1 deletion. In this study, we analysed the gene expression signature of 24 B-ALL patients with IKZF1 deletion against 32 B-ALL patients with wild-type IKZF1. RNA sequencing revealed an adhesion signature corresponding to deregulation of MUC4, secreted phosphoprotein 1 (SPP1), LAMB3, CLSTN2 and MERTK. The upregulation of MUC4 expression was further validated in a B-ALL patient cohort. Moreover, by chromatin immunoprecipitation, we observed the direct binding of IKZF1 on MUC4 promoter and enhancer sequences. Thus, the increase in MUC4 expression upon IKZF1 deletion could be explained by a loss of IKZF1 repression on the MUC4 locus. Finally, using the TARGET-ALL-P2 database, we observed a correlation between decreased survival and high MUC4 expression in B-ALL patients. Thus, we propose MUC4 expression as an indicator of patient prognosis that correlates with the loss of IKZF1 in B-ALL.