Molecular Genetics of High-risk Chronic Lymphocytic Leukemia

Davide Rossi; Gianluca Gaidano

Disclosures

Expert Rev Hematol. 2012;5(6):593-602. 

In This Article

BIRC3 Abnormalities

Activation of the NF-κB pathway in CLL is regarded as a mechanism of resistance to disease eradication.[60–64] Specific interactions between protective microenvironmental niches and CLL cells activate NF-κB signaling, which in turn provides prosurvival signals to the leukemic clone through the upregulation of a number of antiapoptotic genes.[60–64] Importantly, NF-κB activation correlates with CLL outcome and enhanced resistance to fludarabine.[60–64] At least in a fraction of cases, CLL cells might become independent from microenvironmental interactions by gaining active NF-κB signaling through the acquisition of functionally relevant mutations targeting NF-κB genes.[10,11]

The BIRC3 gene cooperates in a protein complex that negatively regulates the MAP3K14 serin-threonine kinase, the central activator of noncanonical NF-κB signaling.[65–69]BIRC3 is recurrently disrupted in CLL by mutations, deletions or a combination of mutations and deletions.[17] At the biochemical level, BIRC3 inactivating mutations and a fraction of BIRC3 deletions cause the truncation of the C-terminal RING domain of the BIRC3 protein, whose E3 ubiquitin ligase activity is essential for switching off MAP3K14 through proteosomal degradation, thus leading to constitutive noncanonical NF-κB activation.[17]

Identification of BIRC3 involvement in CLL may be important for elucidating the molecular genetics of 11q22-q23 deletion. In fact, although ATM has been regarded as the relevant gene of this chromosomal abnormality, biallelic inactivation of ATM does not exceed approximately 30% of cases with 11q22-q23 deletion.[70–74] On this basis, a second tumor suppressor in the 11q22-q23 region has been postulated along with ATM. The BIRC3 gene that maps on 11q22.2, approximately 6 Mb centromeric to the ATM locus, might represent an attractive candidate.[17]

From a clinical standpoint, BIRC3 lesions contribute to clinical aggressiveness and chemorefractoriness in CLL.[17]BIRC3 disruption selectively occurs in approximately 25% fludarabine-refractory CLL, while is consistently absent in progressive CLL that require treatment but prove to be sensitive to fludarabine-based regimens (Figures 1D & 2).[17] Consistent with these findings, BIRC3 lesions are absent in monoclonal B-cell lymphocytosis and occur at low rate (4%) in unselected newly diagnosed CLL where they identify a subgroup of high-risk patients displaying poor survival similar to that associated with TP53 abnormalities (Figure 1D).[17]

Fludarabine refractoriness in CLL may be explained by TP53 disruption in approximately 40% of patients, while approximately 60% high-risk CLL are devoid of TP53 abnormalities.[9] Although next generation sequencing studies have allowed the identification of SF3B1 mutations in chemorefractory CLL, these novel genetic lesions are not numerically sufficient to fully recapitulate the genetics of fludarabine-refractory CLL that are wild type on the TP53 gene. BIRC3 abnormalities recapitulate the genetics of approximately 40% chemorefractory and TP53 wild-type CLL and, along with SF3B1 mutations, may contribute to expand the panel of biomarkers for the early identification of chemorefractory cases (Figure 2).[17] In addition, BIRC3 abnormalities provide a molecular rationale for targeting NF-κB in poor-risk refractory CLL. NF-κB inhibitors are under development in CLL, and preclinical findings suggest that these compounds might be active against chemoresistant CLL clones.[75,76]

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