The introduction of new technology over the past two decades has led to major advances in CLL and changed our view of the disease based upon unexpected findings. Examples of this from a decade ago were cDNA microarray studies by the Staudt laboratory that identified ZAP-70, a protein previously not known to be present in B cells, as strongly associated with high-risk IVGH unmutated CLL. ZAP-70 function in enhancing aberrant B-cell receptor signaling is now appreciated, similar to that observed in T cells. Whole-genome sequencing of tumor cells is the new technology generating excitement across many diseases, and again the field of CLL has benefited from application of this endeavor. Derived from a well-designed whole-genome sequencing experiment of four CLL patients and normal paired germ line control material comes the identification of 46 somatic mutations including four genes (NOTCH 1, XPO1, MYD88, and KLHL6) where recurrent abnormalities were noted. Whereas none of these proteins were previously characterized in CLL, the most surprising was a recurrent NOTCH 1 mutation, occurring at the highest frequency of all mutations identified. Notably, the NOTCH 1 mutation carried functional significance and also was associated with IVGH unmutated CLL and poor clinical outcome. Similar to ZAP-70, an activating NOTCH 1 mutation is not a genetic change one would expect to identify in a B-cell malignancy. Activating NOTCH-1 mutations generally favor development of T-cell lymphoproliferative disorders and disrupted B-cell development. MYD88 mutations contrast with NOTCH-1 mutations, as they were identified in IVGH-mutated disease and were shown to be functionally activating, enhancing TLR signaling and production of inflammatory cytokines. The impact of MYD88, XPO1, and KLHL6 genes on disease outcome remains to be determined.
In Brief
The importance of this study is the discovery of an abundant amount of new information related to different somatic mutations in CLL. The results of this study confirm in a definitive manner that CLL is not like other lymphoproliferative diseases, such as hairy-cell leukemia, where recurrent BRAF mutations are present in 100 percent of patients. The identification of different recurrent mutations that potentially are targetable, but with different classes of drugs, makes CLL a disease to which true individualized therapy might be applied in the future. The whole-genome sequencing study by Puente and colleagues from Oviedo, Spain, is clearly a landmark work that will lead to many new discoveries in CLL. Beyond this, it will be essential to pursue further application of this technology to other aspects of CLL, such as familial predisposition, disease progression, and development of complications associated with the disease, such as infections and autoimmune processes, in order to further improve our ability to predict patient outcome.
Competing Interests
Dr. Byrd indicated no relevant conflicts of interest.
