Advances in B‐cell Precursor Acute Lymphoblastic Leukemia Genomics

Abstract In childhood B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL), cytogenetic abnormalities remain important diagnostic and prognostic tools. A number of well‐established abnormalities are routinely used in risk stratification for treatment. These include high hyperdiploidy and ETV6‐RUNX1 fusion, classified as good risk, while Philadelphia chromosome (Ph) positive ALL and rearrangements of the KMT2A ( MLL ) gene define poor risk. A poor risk subgroup of intrachromosomal amplification of chromosome 21 (iAMP21‐ALL) has been described, in which intensification of therapy has greatly improved outcome. Until recently, no consistent molecular features were defined in around 30% of BCP‐ALL (known as B‐other‐ALL). Recent studies are classifying them into distinct subgroups, some with clear potential for novel therapeutic approaches. For example, in 1 poor risk subtype, known as Ph‐like/BCR‐ABL1‐like ALL, approximately 10% have rearrangements of ABL‐class tyrosine kinases: including ABL1 , ABL2 , PDGFRB , PDGFRA , and CSF1R . Notably, they show a poor response to standard chemotherapy, while they respond to treatment with tyrosine kinase inhibitors, such as imatinib. In other Ph‐like‐ALL patients, deregulation of the cytokine receptor, CRLF2, and JAK2 rearrangements lead to activation of the JAK‐STAT signaling pathway, implicating a specific role for JAK inhibitors in their treatment. Other novel subgroups within B‐other‐ALL are defined by the IGH‐DUX4 translocation, related to deletions of the ERG gene and a good outcome, while fusions involving ZNF384 , MEF2D , and intragenic PAX5 amplification ( PAX5 AMP ) are linked to a poor outcome. Continued genetic screening will eventually lead to complete genomic classification of BCP‐ALL and define more molecular targets for less toxic therapies.