Researchers Identify Genomic Alterations Associated with Drug-Targetable Kinase Activation in Ph-like Acute Lymphoblastic Leukemia

September 11, 2014

Acute lymphoblastic leukemia (ALL) is the most prevalent cancer among children and young adults, and standard treatments within this population generally result in favorable outcomes. By contrast, one particular subtype of this disease, Philadelphia chromosome-like ALL (Ph-like ALL), is associated with inferior outcomes. Ph-like ALL exhibits a gene expression profile similar to chromosome 9:22 translocation positive ALL, yet it lacks the characteristic BCR-ABL fusion protein. Using BCR-ABL1-positive ALL as a paradigm for treatment strategies, a previous study identified genetic changes in 15 Ph-like ALL patients that were targetable with tyrosine kinase inhibitors. To estimate the population prevalence of these changes, this follow-up study examines the genetic profiles of a larger cohort of Ph-like ALL patients .

In a recent New England Journal of Medicine publication, Roberts and others, including TARGET researchers and collaborators, analyzed the gene expression profiles of 1725 patients with B-cell ALL. This cohort was composed of children, adolescents  and young adults; tumor samples from 154 patients were identified to have Ph-like ALL. In this cohort, the frequency of Ph-like ALL increased with age, from 10% of children with standard risk ALL to 27% of young adults with ALL. Molecular analytes from the tumors were characterized by one or more of the following methods: whole genome sequencing, whole exome sequencing, and RNA-seq.

Of these 154 Ph-like ALL cases, 91% of patients harbored somatic changes linked to altered tyrosine kinase activity. For example, the researchers identified EPOR, JAK2, and CRLF2 rearrangements, ABL-class gene fusions, and mutations in JAK-STAT pathway genes. These alterations result in aberrant tyrosine kinases activation, and can possibly be targeted using inhibitors already approved by the US Food and Drug Administration. The majority of the genetic alterations identified in the patients investigated were responsive to known tyrosine kinase inhibitors in cell-based assays, suggesting that clinical trials in Ph-like ALL patient populations would be beneficial.

Last updated: October 30, 2018