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Transcriptome Analysis Identifies a Myeloid-Like Signature in Relapsed or Refractory B-Cell Acute Lymphoblastic
Shisen Wang1, Wenbing Liu1, Ying Wang1
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Tianjin Institutes of Health Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Background:
Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) patients exhibit heterogeneous responses to CD19 chimeric antigen receptor T-cell (CAR-T) therapy. However, current studies primarily focus on the CAR-T cells or the leukemia blasts, and the patient's intrinsic molecular characteristics before treatment remain poorly understood.
Methods:
Fifteen R/R B-ALL patients enrolled in a phase II, single-arm clinical trial (NCT04684147) were stratified at a three-month landmark into 8 good responders and 7 poor responders. Clinical characteristics, genetic alterations and pre-treatment bone marrow transcriptomics were compared between groups, and an exploratory gene-expression score was derived.
Results:
Differential expression and enrichment analyses identified a myeloid-like signature and upregulation of myeloid-related genes in poor responders. Seven myeloid-related genes were examined in independent patient cohorts, in B-ALL cell lines and at single-cell resolution in one patient; three were expressed by the leukemic cells themselves and four predominantly by monocytes and macrophages. A separate, variance-derived seven-gene least absolute shrinkage and selection operator (LASSO) score separated response groups in the discovery cohort (apparent area under the curve, AUC 1.00), with bias-corrected and external estimates of approximately 0.57-0.59 (external cohort AUC 0.592, 95% confidence interval 0.356-0.828).
Conclusions:
Pre-treatment transcriptomic profiling revealed a myeloid-like signature in R/R B-ALL patients with poor CD19 CAR-T response, warranting further investigation as a candidate correlate of treatment outcome.
