MYC addiction in chronic lymphocytic leukemia

MYC is a transcription factor that lies at the crossroads of cell cycle and cell growth by acting downstream of many ligand–membrane receptor complexes and signal transduction pathways [1]. MYC is also a proto-oncogene that contributes to the genesis of many human cancers. The oncogenic activity of MYC begins when its normal transcriptional regulation is disrupted by abnormal microenvironmental interactions or gene lesions, which then lead to abnormally increased levels of intracellular MYC protein. Overexpression of MYC promotes tumorigenesis by activating the transcription of target genes that drive cell proliferation and growth [1].

Among B-cell tumors, MYC has been historically implicated in the molecular pathogenesis of aggressive non-Hodgkin lymphomas [2]. However, there is increasing evidence that MYC has a critical albeit incompletely understood role also in chronic lymphocytic leukemia (CLL), including the observations that: (i) a regulatory region centromeric to MYC contains multiple single nucleotide polymorphisms (SNPs) that have been implicated by genome-wide association studies (GWAS) in susceptibility to CLL [3]; (ii) MYC is activated by the engagement of a number of CLL surface receptors that are known to be relevant for the leukemic clone, including the B-cell receptor, NOTCH and BAFF [4–6]; (iii) expression of MYC and its target genes is increased in high risk CLL and in tumor compartments containing proliferating CLL cells (i.e. the lymph node), and correlates with poor outcome [4,7]; and (iv) transgenic mice expressing MYC together with BAFF develop a CLL-like disease [4].

Functional studies have documented that MYC deregulation in CLL is part of a program of downstream events mainly driven by microenvironmental interactions [4–7]. However, in a fraction of CLL, the MYC gene may be activated in a microenvironment-independent fashion by somatic structural lesions, including translocations with immunoglobulin and non-immunoglobulin loci (˜1% of newly presented cases), gain/amplification at 8q24 (˜5% of newly presented cases) and point mutations (˜1% of newly presented cases) [8–10]. MYC lesions are associated with progressive CLL and accumulate in the advanced phases of the disease. In addition, consistent with a more general role of MYC deregulation in driving the transformation from indolent to aggressive B-cell lymphoproliferation, MYC abnormalities are particularly enriched in ˜30–40% of cases of Richter syndrome, which is the histological shift of CLL to diffuse large B-cell lymphoma [11].

MYC belongs to a transcription regulating network that also includes MAX, a cofactor required for DNA binding by the various members of this network, as well as a group of putative MYC antagonists, namely MNT, MXD1-4 and MGA [12]. In physiological conditions, the MYC protein activates gene transcription through heterodimerization with MAX and then by binding to the E-box DNA recognition sequences in its target gene promoters. Conversely, heterodimers of MAX with MNT, MXD1-4 and MGA antagonize MYC-dependent gene expression regulation by transcriptional repression of the same E-box sequences. On these bases, the MYC oncoprotein transforming ability depends also on the balance between the MYC–MAX and MNT/MXD1-4/MGA–MAX complexes [12].

In CLL, this balance may be disrupted by genetic lesions targeting MYC antagonists. Indeed, the MYC antagonist MNT is known to be recurrently affected by focal losses in a small proportion of CLL, as documented by high resolution SNP array [9]. In addition, three recent studies, including the report by De Paoli et al. in this issue of Leukemia and Lymphoma, have independently shown that MGA, another MYC oncoprotein antagonist, is targeted by focal and recurrent gene deletions or truncating point mutations in a fraction of patients with CLL [9,13,14]. Though the clinical impact of these lesions needs to be formally defined in this leukemia, MGA abnormalities seem to be enriched in cases displaying high risk clinical features, namely fludarabine-refractoriness or transformation into Richter syndrome [14].

Overall, these findings suggest multiple functional and genetic mechanisms of MYC activation in CLL that, albeit occurring at a low frequency as single events, may account for a significant fraction of cases when integrated into a common pathway. The association between MYC functional or genetic deregulation and high risk clinical features in CLL may suggest that MYC oncogene addiction is one of the paths leading to the development of a clinically aggressive phenotype in this leukemia and may represent a therapeutic target in cases that have transformed to Richter syndrome. Indeed, pharmacologic inhibition of the MYC oncoprotein is an attractive therapeutic strategy in tumors with deregulated or elevated MYC expression [1]. Among the strategies to target the MYC network, the BET bromodomain regulatory proteins recently emerged as potent inhibitors of MYC in different tumor types and have shown a significant preclinical activity in tumors known to depend on MYC addiction [15]. Will these compounds also have a role in CLL with deregulated MYC? The molecular data provided by De Paoli et al., as well as other groups, represent a strong rationale for MYC targeting in CLL. However, the answer to this question can only be provided by the establishment of preclinical mouse models of high risk CLL and Richter syndrome with activated MYC. So, despite the promise, much remains to be done.

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