Why Are There Variable Responses to Treatment in BCR-ABL1 Lymphoblastic Leukemia?

A recent study suggests heterogeneity in treatment responses and tyrosine kinase inhibitor (TKI) efficacy are “unexpected outcomes of the differentiation stage” at which BCR–ABL1 lymphoblastic leukemia transforms.

The study was led by Jaeseung Kim, PhD, of the Princess Margaret Cancer Centre, the Ontario Institute for Cancer Research, and the University of Toronto.

Dr. Kim and colleagues conducted the study because the variable responses to TKIs in BCR–ABL1 lymphoblastic leukemia are “poorly understood,” particularly when there no mutations in the kinase domain of BCR–ABL1.

They used deep molecular profiling and detected three transcriptomic subtypes of BCR–ABL1 lymphoblastic leukemia. Each subtype represented a maturation arrest at a stage of B-cell progenitor differentiation, according to Dr. Kim and colleagues.

Arrests at an earlier stage of B-cell progenitor differentiation was associated with “lineage promiscuity, treatment refractoriness, and poor patient outcomes,” the study’s authors wrote. In contrast, arrest at a later stage of B-cell progenitor differentiation was associated with “lineage fidelity, durable leukemia remissions and improved patient outcomes,” according to Dr. Kim and colleagues.

Genomic events that control transition points in B-cell development marked each maturation arrest.

“Interestingly, these events were absent in BCR–ABL1[-positive] preleukemic stem cells isolated from patients regardless of subtype, which supports that transcriptomic phenotypes are determined downstream of the leukemia-initialing event,” Dr. Kim and colleagues wrote.

The researchers noted that resolving transcriptomic subtypes contributes to better understanding the heterogeneity of treatment responses in BCR–ABL1 lymphoblastic leukemia.

“Overall, our data indicate that treatment response and TKI efficacy are unexpected outcomes of the differentiation stage at which this leukemia transforms,” Dr. Kim and colleagues concluded.

Reference

Kim JC, Chan-Seng-Yue M, Ge S, et al. Transcriptomic classes of BCR-ABL1 lymphoblastic leukemia. Nat Genet. 2023;55(7):1186-1197. doi:10.1038/s41588-023-01429-4