@article{1a3e09e7cd41403ba6537256f2feece5,
title = "Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia",
abstract = "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.",
keywords = "acute lymphoblastic leukemia, chemotherapy, immune microenvironment, monocytes, relapse, single cell, Prognosis, Humans, Child, Preschool, Infant, Male, Case-Control Studies, Young Adult, Antineoplastic Agents/pharmacology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology, Monocytes/immunology, Tumor Microenvironment/immunology, Bone Marrow Transplantation, Adult, Female, Retrospective Studies, Single-Cell Analysis, Child, Proteome/analysis, Mice, Inbred C57BL, Survival Rate, Neoplasm Recurrence, Local/immunology, Animals, RNA-Seq, Adolescent",
author = "Witkowski, {Matthew T.} and Igor Dolgalev and Evensen, {Nikki A.} and Chao Ma and Tiffany Chambers and Roberts, {Kathryn G.} and Sheetal Sreeram and Yuling Dai and Tikhonova, {Anastasia N.} and Audrey Lasry and Chunxu Qu and Deqing Pei and Cheng Cheng and Robbins, {Gabriel A.} and Joanna Pierro and Shanmugapriya Selvaraj and Valeria Mezzano and Marla Daves and Lupo, {Philip J.} and Scheurer, {Michael E.} and Loomis, {Cynthia A.} and Mullighan, {Charles G.} and Weiqiang Chen and Rabin, {Karen R.} and Aristotelis Tsirigos and Carroll, {William L.} and Iannis Aifantis",
note = "Funding Information: We thank the NYU School of Medicine core facilities, including High Performance Computing, Flow Cytometry and the Genome Technology Center (this shared resource is partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center). We are grateful to J. Rubnitz and M. Lear from St Jude Children's Hospital, and T. Tello, J. Lund, and Y.D. from the Children's Oncology Group for assistance with patient bone marrow biopsy acquisition. We are grateful to P. Chattopadhyay at the NYU Precision Immunology Incubator for assistance with the BD Symphony. We are grateful to the NYU Histopathology Core for assistance with primary human tissue sectioning and imaging, Y. Deng and M. Cammer from the NYU Langone's Microscopy Laboratory for assistance with imaging. We are grateful to B. Reizis for manuscript suggestions. Experimental Pathology Research Lab by the Cancer Center Support Grant P30CA016087 and the PerkinElmer Vectra multispectral imaging system awarded through a Shared Instrumentation Grant S10 OD021747. This research was supported by the US NIH (RO1CA202025, RO1CA202027, RO1CA216421, 1RO1CA228135, and PO1CA229086), the Leukemia & Lymphoma Society (TRP no. 6580), the Alex's Lemonade Stand Foundation for Childhood Cancer, and the St. Baldrick's Cancer Research Foundation (to I.A). M.W. is a Fellow of The Leukemia & Lymphoma Society. This project was supported by funds from The Jeffrey Pride Foundation for Pediatric Cancer Research and the Children's Oncology Group Foundation. The work was also supported by the New York State Department of Health (NYSTEM Program). A.N.T. was supported by the Leukemia and Lymphoma Society and the Alex's Lemonade Stand Foundation for Childhood Cancer. Figure S1A and Graphical Abstract generated using BioRender. Conceptualization, M.T.W. I.D. W.L.C. and I.A.; Methodology, M.T.W. I.D. N.A.E. A.N.T. C.M. K.G.R. C.A.L. K.R.R. and I.A.; Investigation, M.T.W. I.D. N.A.E. C.M. T.C. K.G.R. S.S. C.Q. D.P. C.C. V.M. M.E.S. Y.D. A.L. K.R.R. W.L.C. and I.A.; Resources, M.T.W. I.D. N.A.E. C.M. T.C. K.G.R. G.A.R. J.P. M.D. P.J.L. M.E.S. C.G.M. K.R.R. W.L.C. and I.A. Writing – Original Draft, M.T.W. I.D. and I.A.; Writing – Review & Editing, M.T.W. I.D. N.A.E. A.N.T. A.T. W.L.C. and I.A; Visualization, I.D. S.S. V.M. and C.A.L.; Supervision, A.T. W.L.C. and I.A. The authors declare no competing interests. Funding Information: We thank the NYU School of Medicine core facilities, including High Performance Computing, Flow Cytometry and the Genome Technology Center (this shared resource is partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center). We are grateful to J. Rubnitz and M. Lear from St Jude Children's Hospital, and T. Tello, J. Lund, and Y.D. from the Children's Oncology Group for assistance with patient bone marrow biopsy acquisition. We are grateful to P. Chattopadhyay at the NYU Precision Immunology Incubator for assistance with the BD Symphony. We are grateful to the NYU Histopathology Core for assistance with primary human tissue sectioning and imaging, Y. Deng and M. Cammer from the NYU Langone's Microscopy Laboratory for assistance with imaging. We are grateful to B. Reizis for manuscript suggestions. Experimental Pathology Research Lab by the Cancer Center Support Grant P30CA016087 and the PerkinElmer Vectra multispectral imaging system awarded through a Shared Instrumentation Grant S10 OD021747. This research was supported by the US NIH ( RO1CA202025 , RO1CA202027 , RO1CA216421 , 1RO1CA228135 , and PO1CA229086 ), the Leukemia & Lymphoma Society (TRP no. 6580), the Alex's Lemonade Stand Foundation for Childhood Cancer , and the St. Baldrick{\textquoteright}s Cancer Research Foundation (to I.A). M.W. is a Fellow of The Leukemia & Lymphoma Society. This project was supported by funds from The Jeffrey Pride Foundation for Pediatric Cancer Research and the Children{\textquoteright}s Oncology Group Foundation . The work was also supported by the New York State Department of Health (NYSTEM Program). A.N.T. was supported by the Leukemia and Lymphoma Society and the Alex's Lemonade Stand Foundation for Childhood Cancer . Figure S1A and Graphical Abstract generated using BioRender. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = jun,
day = "8",
doi = "10.1016/j.ccell.2020.04.015",
language = "English (US)",
volume = "37",
pages = "867--882.e12",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}