Like cartographers completing a map, investigators have identified multiple new subtypes of the most common childhood cancer—research that will likely improve the diagnosis and treatment of high-risk patients. St. Jude Children’s Research Hospital scientists led the study, which appears as an advance online publication today in the journal Nature Genetics.

Researchers used integrated genomic analysis, including RNA sequencing, to define the genomic landscape of B-cell acute lymphoblastic leukemia (B-ALL) in almost 2,000 children and adults. B-ALL is the most common form of ALL and the most common cancer in children. B-ALL remains the leading cause of pediatric cancer death.

Investigators identified 23 subtypes of B-ALL, including eight new subtypes, with distinct genomic and clinical features as well as outcomes. Subtype prevalence often varies with age. More than 90 percent of B-ALL cases can now be categorized by subtype compared with 70 percent a few years ago.

“B-ALL has remarkable molecular diversity, which we and others have used to refine classification and drive the development of precision medicines to improve B-ALL treatment and outcomes,” said corresponding author Charles Mullighan, MBBS, M.D., a member of the St. Jude Department of Pathology. “Part of precision medicine is an accurate molecular diagnosis, which this study provides to more patients.”

A novel subtype-defining alteration

Alterations of the transcription factor gene PAX5 defined two new subtypes, including PAX5 P80R, as the first lymphoblastic leukemia initiated by a point mutation. “While secondary mutations are necessary and often involve kinase signaling, we show this point mutation impairs development of B lymphoid cells and promotes development of B-ALL in mice,” Mullighan said.

The other PAX5 subtype, PAX5-altered, was defined by diverse alterations in the gene, including sequence mutations or rearrangements with one of 24 other genes. Together the PAX5 subtypes accounted for almost 10 percent of the previously uncategorized cases of B-ALL.

The new subtypes include a high-risk variety of B-ALL that occurs primarily in adults. It is defined by rearrangement of the transcription factors BCL2 with MYC or BCL6. “This subtype has a dismal diagnosis,” Mullighan said. “Recognition of this subtype-defining rearrangement may lead to alternative therapy for patients.” In contrast, a subtype defined by rearrangement of the gene DUX4 was associated with a good prognosis in adults, as had previously been observed in children.