Abstract
Evasion of apoptosis is critical for tumorigenesis, and sustained survival of nascent neoplastic cells may depend upon the endogenous levels of pro-survival BCL-2 family members. Indeed, previous studies using gene-targeted mice revealed that BCL-XL, but surprisingly not BCL-2, is critical for the development of c-MYC-induced pre-B/B lymphomas. However, it remains unclear whether another pro-survival BCL-2 relative contributes to their development. MCL-1 is an intriguing candidate, because it is required for cell survival during early B-lymphocyte differentiation. It is expressed abnormally high in several types of human B-cell lymphomas and is implicated in their resistance to chemotherapy. To test the B-cell intrinsic requirement for endogenous MCL-1 in lymphoma development, we conditionally deleted Mcl-1 in B-lymphoid cells of Eμ-Myc transgenic mice. We found that MCL-1 loss in early B-lymphoid progenitors delayed MYC-driven lymphomagenesis. Moreover, the lymphomas that arose when MCL-1 levels were diminished appeared to have been selected for reduced levels of BIM and/or increased levels of BCL-XL. These results underscore the importance of MCL-1 in lymphoma development and show that alterations in the levels of other cell death regulators can compensate for deficiencies in MCL-1 expression.
Highlights
NOXA), which are activated transcriptionally and/or post-transcriptionally in response to diverse intracellular stresses.[6,7] The pro-apoptotic multi-BCL-2 homology (BH) domain proteins BAX, BAK have the essential role of permeabilizing the mitochondrial outer membrane, which constitutes the ‘point-of-no-return’ in apoptosis signaling and unleashes the caspase cascade that mediates cell demolition.[4,5,9] The pro-survival BCL-2 family members, including BCL-2, BCL-XL, MCL-1, BCL-W and
In cells undergoing neoplastic transformation, apoptosis can be triggered by stress conditions induced by newly acquired oncogenic mutations or by limiting availability of nutrients or growth factors from the tumor microenvironment
Regardless of the trigger that activates apoptosis signaling, evasion of cell death is essential for a population of nascent neoplastic cells to expand and sub-clones to acquire additional oncogenic lesions that cooperate with the initiating oncogenic mutation(s) to promote emergence of malignant cells.[16]
Summary
NOXA), which are activated transcriptionally and/or post-transcriptionally in response to diverse intracellular stresses.[6,7] The pro-apoptotic multi-BCL-2 homology (BH) domain proteins BAX, BAK (and possibly BOK8) have the essential role of permeabilizing the mitochondrial outer membrane, which constitutes the ‘point-of-no-return’ in apoptosis signaling and unleashes the caspase cascade that mediates cell demolition.[4,5,9] The pro-survival BCL-2 family members, including BCL-2, BCL-XL, MCL-1, BCL-W and. Many cancers display abnormalities in the levels of prosurvival and/or pro-apoptotic BCL-2 family members and evasion of apoptosis is widely thought to be essential to sustain the survival of nascent neoplastic cells and critical for tumorigenesis.[14,15] the mechanisms that protect cells undergoing neoplastic transformation from apoptosis remain incompletely understood.[2,16] Abnormalities in the BCL-2-governed apoptotic pathway or its regulators have been implicated in B-cell lymphoma development. Chromosomal translocation in human follicular center B-cell lymphoma, whereas both alleles of BIM are frequently lost in mantle cell lymphoma.[17,18,19,20] transgenic overexpression of BCL-2 (or its relatives BCL-XL or MCL-1), or engineered loss of BIM, PUMA or BAX, can accelerate lymphomagenesis, if cell cycle control is impaired, for example by enforced expression of c-MYC21–25 or v-Abl.[26]. The impaired tumor development could be overcome by concomitant loss of proapoptotic BIM.[30]
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