New data published in Nature Genetics describing the diversity of subtypes of B progenitor acute lymphoblastic leukemia (B-ALL) may help improve prognostic abilities for patients and lead to the development of new targeted therapies with fewer side effects.
In a significant number of patients with B-ALL, the genetic alteration is unknown. However, B-ALL is known to have remarkable molecular diversity, and a more refined classification may lead to greater use of precision medicine for improving treatments and outcomes in B-ALL treatments.
Investigators used integrated genomic analysis and transcriptome sequencing to assess data from 1988 patients (age range, 0.2-79 years old) with B-ALL. They identified 23 subtypes of B-ALL, including 8 novel subtypes that had unique genomic and clinical features and outcomes and were marked by a variation in prevalence according to age.
In particular, the data confirmed the central role of the transcription factor gene PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis. Alterations in PAX5 defined 2 new subtypes of B-ALL: PAX5 P80R, a lymphoblastic leukemia initiated by a point mutation; and PAX5-altered, defined by diverse alterations in the gene including sequence mutations or rearrangements with 1 of 24 other genes. Together, the PAX5 subtypes accounted for almost 10% of previously uncategorized cases of B-ALL.
The new subtypes also included a high-risk variety of B-ALL that occurs primarily in adults and is defined by rearrangement of the transcription factors BCL2 with MYC or BCL6. In contrast, a subtype defined by rearrangement of DUX4 was associated with a good prognosis in adults.
The authors suggested that the vast majority of B-ALL cases and their underlying driver alterations may now be able to be categorized by subtype, allowing appropriate risk stratification and individualized therapeutic approaches.
1. Gu Z, Churchman ML, Roberts KG et al. PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia [published online January 14, 2019]. Nat Genet. doi: 10.1038/s41588-018-0315-5