The lack of the transcriptional regulator IRF4, a critical regulator of NOTCH signaling pathway, leads to high NOTCH2 expression, which in turn mediates the upregulation of intracellular MCL-1 expression and ultimately leads to the development of primary resistance to venetoclax in trisomy 12 CLL cells. Here, MCL1 is linked to B-cell chronic lymphocytic leukemia.