Transcriptomic Classes of BCR-ABL1 Lymphoblastic Leukemia

Overview

Journal Nat Genet

Specialty Genetics

Date 2023 Jun 19

PMID 37337105

Authors

Jaeseung C Kim

Michelle Chan-Seng-Yue

Sabrina Ge

Andy G X Zeng

Karen Ng

Olga I Gan

Laura Garcia-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

Affiliations

Soon will be listed here.

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.

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