Abstract
BackgroundChronic Myeloid Leukemia was always referred as a unique cancer due to the apparent independence from tumor suppressors’ deletions/mutations in the early stages of the disease. However, it is now well documented that even genetically wild-type tumor suppressors can be involved in tumorigenesis, when functionally inactivated. In particular, tumor suppressors’ functions can be impaired by subtle variations of protein levels, changes in cellular compartmentalization and post-transcriptional/post-translational modifications, such as phosphorylation, acetylation, ubiquitination and sumoylation. Notably, tumor suppressors inactivation offers challenging therapeutic opportunities. The reactivation of an inactive and genetically wild-type tumor suppressor could indeed promote selective apoptosis of cancer cells without affecting normal cells.Main bodyChronic Myeloid Leukemia (CML) could be considered as the paradigm for non-genomic loss of function of tumor suppressors due to the ability of BCR-ABL to directly promote functionally inactivation of several tumor suppressors.Short conclusionIn this review we will describe new insights on the role of FoxO, PP2A, p27, BLK, PTEN and other tumor suppressors in CML pathogenesis. Finally, we will describe strategies to promote tumor suppressors reactivation in CML.
Highlights
Chronic Myeloid Leukemia was always referred as a unique cancer due to the apparent independence from tumor suppressors’ deletions/mutations in the early stages of the disease
Chronic Myeloid Leukemia (CML) was generally referred as an unique cancer, due to the apparent independence from tumor suppressors’ deletions/mutations in the early stages of the disease [1]. In agreement with this concept, infection of murine stem cells with BCRABL-expressing vectors was associated with rapid development of CML without the need of additional genetic lesions [2]
BCR-ABL was shown to promote DOK1 ubiquitination and degradation [41]. These data indicate that DOK proteins act as tumor suppressors through the inhibition of the RAS-MEK-ERK pathway, but in CML their function is directly inhibited by BCR-ABL (Fig. 2)
Summary
Chronic Myeloid Leukemia (CML) was generally referred as an unique cancer, due to the apparent independence from tumor suppressors’ deletions/mutations in the early stages of the disease [1]. BCR-ABL was shown to promote DOK1 ubiquitination and degradation [41] All together, these data indicate that DOK proteins act as tumor suppressors through the inhibition of the RAS-MEK-ERK pathway, but in CML their function is directly inhibited by BCR-ABL (Fig. 2). In line with the aim of this review, it should be noted that BCR-ABL is able to positively regulate several oncogenic miRNAs which in turn affect the expression of tumor suppressors [54], with consequent inactivation. Src proteins behave as oncogenes, Blk was shown to act as a tumor suppressor through the regulation of CML cells proliferation, in a pathway involving c-myc and p27 (Fig. 3). Treatment with ROCK inhibitor was shown to rescue the apoptotic response to imatinib [57]
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