Summary

A subset of B cell acute lymphoblastic leukemia (B-ALL) patients will relapse and succumb to therapy-resistant disease. The bone marrow microenvironment may support B-ALL progression and treatment evasion. Utilizing single-cell approaches, we demonstrate B-ALL bone marrow immune microenvironment remodeling upon disease initiation and subsequent re-emergence during conventional chemotherapy. We uncover a role for non-classical monocytes in B-ALL survival, and demonstrate monocyte abundance at B-ALL diagnosis is predictive of pediatric and adult B-ALL patient survival. We show that human B-ALL blasts alter a vascularized microenvironment promoting monocytic differentiation, while depleting leukemia-associated monocytes in B-ALL animal models prolongs disease remission in vivo. Our profiling of the B-ALL immune microenvironment identifies extrinsic regulators of B-ALL survival supporting new immune-based therapeutic approaches for high-risk B-ALL treatment.

Overall design

Single-cell RNA-sequencing libraries of primary human peripheral blood immune populations. B-ALL patient bone marrow samples were separated into CD19+ B cell and CD19-CD45+ non-B cell fractions by flow-based sorting and then mixed at a ratio of 1:5 CD19+:CD19-CD45+ followed by scRNA-Seq. Total CD45+ peripheral blood cells were sequenced from healthy donors.

Contributors

Matthew T Witkowski 1, Igor Dolgalev 2, Nikki A Evensen 3, Chao Ma 4, Tiffany Chambers 5, Kathryn G Roberts 6, Sheetal Sreeram 3, Yuling Dai 3, Anastasia N Tikhonova 3, Audrey Lasry 3, Chunxu Qu 6, Deqing Pei 6, Cheng Cheng 6, Gabriel A Robbins 3, Joanna Pierro 3, Shanmugapriya Selvaraj 7, Valeria Mezzano 7, Marla Daves 5, Philip J Lupo 5, Michael E Scheurer 5, Cynthia A Loomis 7, Charles G Mullighan 6, Weiqiang Chen 4, Karen R Rabin 5, Aristotelis Tsirigos 2, William L Carroll 8, Iannis Aifantis 9

Contact

ioannis.aifantis@nyulangone.org.(Iannis Aifantis)