Mcl-1 expression predicts progression-free survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and rituximab

Abstract

Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. Increased Mcl-1 expression is associated with failure to achieve remission after treatment with fludarabine and chlorambucil in patients with chronic lymphocytic leukemia (CLL

Protein expression analysis of chronic lymphocytic leukemia defines the effect of genetic aberrations and uncovers a correlation of CDK4, P27 and P53 with hierarchical risk

“…49,50 In fact, a novel inhibitor of AKT has been shown to exert anti-proliferative activity on CLL cell lines and to induce cell death of CLL cells in vitro with typical features of apoptosis, such as activation of caspase-3 and release of cytochrome c. 49,50 Earlier studies found an association of high levels of BCL2 and MCL1 proteins with poor prognostic factors, shortened survival and failure to achieve remission in response to established CLL therapies. 27,28,51,52 As reported previously, 51 levels of MCL1 were independent of cytogenetics in the present study. Concerning BCL2, higher levels were associated with lower risk categories.…”

Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1

“…Mcl-1 is a member of the Bcl-2 family and high expression levels are predictive of an inferior clinical outcome following chemotherapy. 4 Sorafenib was reported to attenuate Mcl-1 translation in association with inhibition of eIF4E translation initiation factor. 14 To test whether Mcl-1 expression was affected by sorafenib in primary CLL cells, Mcl-1 expression was analyzed 24 h after treatment with increasing doses of sorafenib.…”

“…2,3 In addition to Bcl-2, the overexpression of Mcl-1 has been implicated in the deregulation of apoptosis: high levels of Mcl-1 are associated with inferior treatment responses after chemotherapy. 4 Furthermore, based on recently published data, Mcl-1 is a bona fide marker for poor prognosis of CLL patients. 5 Importantly, the expression of Mcl-1 is not exclusively regulated through cell intrinsic mechanisms, but strongly dependent on extracellular factors such as B-cell receptor signalling, CD40 signalling and activation of the vascular epidermal growth factor receptor (VEGFR).…”

Development of Noxa-like BH3 Mimetics for Apoptosis-Based Therapeutic Strategy in Chronic Lymphocytic Leukemia

“…Initially, high expression levels of Mcl-1 were inversely correlated with the susceptibility of CLL cells to apoptosis in vitro and with the responsiveness of patients to chemotherapy. More recently, it was shown that Mcl-1 levels are also correlated with prognostic markers and are predictive of patients' clinical outcome (6,7). In addition, high Mcl-1 levels have been observed in CLL cells originating from the lymph nodes (8), which are thought to play an important role in drug resistance and relapse.…”