MCL-1 Critically Regulates Survival Of T-Lymphocyte Non-Hodgkin Lymphoma

The heterogeneous subgroup of T-lymphocyte non-Hodgkin lymphoma (T-NHL) exhibits an aggressive growth pattern and is relatively insensitive to chemotherapy. The molecular mechanisms of survival and resistance to therapy remain largely undefined. We hypothesized that BCL-2 proteins with anti-apoptotic properties protect T-NHL cells from cell death, cause resistance to therapy and therefore represent an attractive target for therapy. MCL-1 potently protects physiologically healthy T-lymphocytes from cell death, but its function in transformed T-cells is incompletely understood. We therefore dissected the role of MCL-1 using in silico meta-analyses on available gene expression data on human primary T-NHL samples. We identified MCL-1 as the primary BCL-2 family protein to be highly expressed across most major T-NHL subsets. Expression of MCL-1 was restricted to its anti-apoptotic full-length splice variant as opposed to its pro-apoptotic short isoform. To functionally characterize the requirement for MCL-1, we utilized a T-NHL mouse model, which is based on four consecutive low-dose whole-body γ-irradiations in 4 week-old mice resulting in the development of T-NHL mimicking human peripheral T-cell lymphoma. We utilized mice harbouring loxP-flanked Mcl-1 or loxP-flanked Bcl-x_(L) in combination with inducible Cre recombinase to conditionally delete the gene of interest after lymphoma induction. Interestingly, conditional deletion of only one allele of Mcl-1 in fully established primary T-NHL cells ex vivo led to a significant and specific loss of viability, whereas survival remained unaffected by full deletion of Bcl-x_(L). Reduced MCL-1 levels resulted in substantially elevated sensitivity to standard chemotherapeutics such as anthracyclins, cyclophosphamide and etoposide. In addition, mono-allelic deletion of Mcl-1 in vivo prolonged survival of lymphoma-bearing mice. Together, these data argue that anti-apoptotic MCL-1 is the single most important BCL-2 family member involved in the sustained survival of T-NHL.