Transcriptomic classes of BCR-ABL1 lymphoblastic leukemia
Jaeseung Kim, Michelle Chan‐Seng‐Yue, Sabrina Ge, Andy G.X. Zeng, Karen Ng, Olga I. Gan, Laura García‐Prat, Eugenia Flores‐Figueroa, Tristan Woo, Amy Xin Wei Zhang, Andrea Arruda, Shivapriya Chithambaram, Stephanie M. Dobson, Amanda Khoo, Shahbaz Khan, Narmin Ibrahimova, Ann George, Anne Tierens, Johann Hitzler, Thomas Kislinger, John E. Dick, John D. McPherson, Mark D. Minden, Faiyaz Notta
Abstract
Abstract In BCR-ABL1 lymphoblastic leukemia, treatment heterogeneity to tyrosine kinase inhibitors (TKIs), especially in the absence of kinase domain mutations in BCR-ABL1 , is poorly understood. Through deep molecular profiling, we uncovered three transcriptomic subtypes of BCR-ABL1 lymphoblastic leukemia, each representing a maturation arrest at a stage of B-cell progenitor differentiation. An earlier arrest was associated with lineage promiscuity, treatment refractoriness and poor patient outcomes. A later arrest was associated with lineage fidelity, durable leukemia remissions and improved patient outcomes. Each maturation arrest was marked by specific genomic events that control different transition points in B-cell development. Interestingly, these events were absent in BCR-ABL1 + preleukemic stem cells isolated from patients regardless of subtype, which supports that transcriptomic phenotypes are determined downstream of the leukemia-initialing event. Overall, our data indicate that treatment response and TKI efficacy are unexpected outcomes of the differentiation stage at which this leukemia transforms.