BCL11B mutation

In this review, we sought to compile the phenotypic and genotypic variables associated with previously reported mutations in this gene in order to provide a better understanding of the consequences of deleterious variants. We also highlight the importance of a careful evaluation of the mutation type, its location and the pattern of inheritance of the variants in order to assign the most accurate pathogenicity and actionability of the genetic findings.

To the best of our knowledge, this is the first reported case of WBS in T-cell acute lymphoblastic leukemia. We want to emphasize that the occurrence of leukemia in this patient might be related to the loss of 7q11.23 and microdeletion of 9p21.3 (including 3 TSGs), but the relationship between WBS and malignancy remains unclear. Further studies are required to clarify the relationship between WBS and malignancy.

No abstract available

Our report represents one of the most extensive and detailed studies regarding the landscape of BCL11B point and indel mutations in human cancer. BCL11B alterations occur widely in mature, immature, B-cell, Tcell, and sarcomatous malignancies. TP53, PIM1, and SOCS1 are the most commonly co-mutated genes.

We performed preclinical drug testing of the BCL-2 inhibitor, venetoclax, and the FLT3 inhibitor, gilteritinib, in two FLT3-mutant BCL11B-a PDX models: one T/myeloid MPAL and one acute undifferentiated leukemia (AUL). We showed that the combination of FLT3 and BCL-2 inhibition is highly effective at reducing leukemia burden in two preclinical models of BCL11B-a lineage ambiguous leukemia. Studies in additional PDXs are ongoing to identify the mechanism of synergy and clarify the molecular basis for heterogeneity in clinical response in the different preclinical models.

BCL11B mutations were associated with favorable clinical outcome for TCL patients; it might be considered as a novel biomarker for TCL prognostic stratification.

This review also showed that deregulation of MCPH1/BRIT1 is significantly associated with reduced overall survival in 57% (12/21) and relapsed free survival in 33% (7/21) of cancer types especially in oesophageal squamous cell carcinoma and renal clear cell carcinoma. A common finding of this study is that the loss of MCPH1/BRIT1 gene expression plays a key role in promoting genome instability and mutations supporting its function as a tumour suppressor gene.

HTS is a useful approach that allows simultaneously analyzing mutations, CNVs and the clonal repertoire in T-ALL patients. This approach may simplify the genetic assessment of ALL.

In conclusion, our study presented for the first time a potential oncogenic role for RIT1 in glioblastoma. Knowing that the RAS superfamily of proteins has created an evolution in the cancer field, RIT1 should be added to this list through further investigations on its possible usage as a biomarker and therapeutic target in glioblastoma.

The second patient had developmental delay, dysmorphic features, spasticity in lower limbs and dental anomalies. Our report contributes to the knowledge of the BCL11BRD, expands the clinical phenotype, and can also aid with genetic counseling of newly identified patients.