Among patients with chronic lymphocytic leukemia (CLL), the TA-isoform of the p63 transcription factor (TAp63) may modulate BCL2, and consequently drive aggressiveness and treatment resistance, according to research published in Blood Advances.
Previous research has suggested that p63, which is a member of the p53 transcription factor family, may be involved in the development of cancer. There is, furthermore, evidence that p63 deregulation promotes aggressiveness in the setting of CLL.
The expression of TAp63, the p63 isoform in CLL, is known to be regulated by immune signals, and research has suggested that TAp63 is overexpressed among patients with adverse prognoses. There is also evidence that TAp63 affects CLL cell migration and invasiveness.
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Moreover, researchers have previously shown that BCL2 may be involved in the downregulation of apoptosis in CLL, a process also linked with TAp63 expression levels. For this study, researchers evaluated TAp63 expression level fluctuation during CLL progression, and evaluated whether there is a link between TAp63 and BCL2 at the molecular level. Diagnostic samples were obtained from 166 patients with CLL.
Analysis of the samples obtained showed that TAp63 expression predicts a poor clinical prognosis, both including the likelihood of disease relapse and survival. BCL2 protein and messenger RNA levels were, furthermore, correlated with TAp63 expression, and chromatin immunoprecipitation sequencing showed that TAp63 has a bonding profile at BCL2.
The authors also noted that TAp63 upregulation prevents response to venetoclax, an inhibitor of BCL2.
“In conclusion, TAp63 emerges as a novel player underlying aggressiveness and treatment resistance in CLL,” the authors wrote in their report. “This claim is supported by the finding of concerted regulation between TAp63 and the prosurvival protein BCL2, thus hinting at a novel mechanism that likely contributes to the antiapoptotic phenotype of CLL cells.”
Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures.
Reference
Laidou S, Grigoriadis D, Papanikolaou S, et al. The TΑp63/BCL2 axis represents a novel mechanism of clinical aggressiveness in chronic lymphocytic leukemia. Blood Adv. 2022;6(8):2646-56. doi:10.1182/bloodadvances.2021006348
