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MCL-1 Promoter Insertions and Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is caused by an accumulation of malignant lymphocytes that fail to undergo programmed cell death. High expression of the Mcl-1 protein, a member of the Bcl-2 family of apoptosis regulators, is associated with pathogenesis of CLL. To investigate the mechanism of altered Mcl-1 expression in CLL, Moshynska et al. (p. 673) sequenced the MCL-1 gene from peripheral blood lymphocytes of 58 CLL patients and 18 control subjects and analyzed mRNA and protein expression in a subset of patients. Seventeen of the patients but none of the control subjects had a short (6- or 18-nucleotide) insertion in the MCL-1 promoter that was associated with increased mRNA and protein expression. The presence of an insertion was also associated with more rapid disease progression, poorer response to chemotherapy, and shorter survival.

In an editorial (p. 642), Kitada and Reed point out that the promoter insertions were not always associated with high levels of Mcl-1 protein expression, possibly because signals in the microenvironment might combine with the insertions to increase MCL-1 expression or because Mcl-1 may turn over rapidly. Ultimately, they note, the discovery of the insertions will be important in developing improved prognostic information about CLL as well as in better understanding the molecular mechanism of aberrant apoptosis in this disease.