Single cell dissection of developmental origins and transcriptional heterogeneity in B-cell acute lymphoblastic leukemia

Iacobucci, I.; Zeng, A. G. X.; Gao, Q.; Garcia-Prat, L.; Baviskar, P.; Shah, S.; Murison, A. J.; Voisin, V.; Chan-Seng-Yue, M.; Cheng, C.; Qu, C.; Bailey, C.; Lear, M.; Witkowski, M.; Zhou, X.; Zaldivar Peraza, A.; Gangwani, K.; Advani, A.; Luger, S. M.; Litzow, M. R.; Rowe, J. M.; Paietta, E. M.; Stock, W.; Dick, J. E.; Mullighan, C. G.

doi:10.1101/2023.12.04.569954

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bioRxiv · 10.1101/2023.12.04.569954

Single cell dissection of developmental origins and transcriptional heterogeneity in B-cell acute lymphoblastic leukemia

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Abstract

Sequencing of bulk tumor populations has improved genetic classification and risk assessment of B-ALL, but does not directly examine intratumor heterogeneity or infer leukemia cellular origins. We profiled 89 B-ALL samples by single-cell RNA-seq (scRNA-seq) and compared them to a reference map of normal human B-cell development established using both functional and molecular assays. Intra-sample heterogeneity was driven by cell cycle, metabolism, differentiation, and inflammation transcriptional programs. By inference of B lineage developmental state composition, nearly all samples possessed a high abundance of pro-B cells, with variation between samples mainly driven by sub-populations. However, ZNF384-r and DUX4- r B-ALL showed composition enrichment of hematopoietic stem cells, BCR::ABL1 and KMT2A-r ALL of Early Lymphoid progenitors, MEF2D-r and TCF3::PBX1 of Pre-B cells. Enrichment of Early Lymphoid progenitors correlated with high-risk clinical features. Understanding variation in transcriptional programs and developmental states of B-ALL by scRNA-seq refines existing clinical and genomic classifications and improves prediction of treatment outcome.

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Iacobucci, I., Zeng, A. G. X., Gao, Q., Garcia-Prat, L., Baviskar, P., Shah, S., Murison, A. J., Voisin, V., Chan-Seng-Yue, M., Cheng, C., Qu, C., Bailey, C., Lear, M., Witkowski, M., Zhou, X., Zaldivar Peraza, A., Gangwani, K., Advani, A., Luger, S. M., Litzow, M. R., Rowe, J. M., Paietta, E. M., Stock, W., Dick, J. E., Mullighan, C. G.. 2023-12-09. Single cell dissection of developmental origins and transcriptional heterogeneity in B-cell acute lymphoblastic leukemia. https://doi.org/10.1101/2023.12.04.569954

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