Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia

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

doi:10.1016/j.ccell.2020.04.015

Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	867-882.e12
Journal	Cancer Cell
Volume	37
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2020.04.015
State	Published - Jun 8 2020

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

ASJC Scopus subject areas

Oncology
Cancer Research
Cell Biology

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10.1016/j.ccell.2020.04.015

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Witkowski, M. T., Dolgalev, I., Evensen, N. A., Ma, C., Chambers, T., Roberts, K. G., Sreeram, S., Dai, Y., Tikhonova, A. N., Lasry, A., Qu, C., Pei, D., Cheng, C., Robbins, G. A., Pierro, J., Selvaraj, S., Mezzano, V., Daves, M., Lupo, P. J., ... Aifantis, I. (2020). Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia. Cancer Cell, 37(6), 867-882.e12. https://doi.org/10.1016/j.ccell.2020.04.015

Witkowski, MT, Dolgalev, I, Evensen, NA, Ma, C, Chambers, T, Roberts, KG, Sreeram, S, Dai, Y, Tikhonova, AN, Lasry, A, Qu, C, Pei, D, Cheng, C, Robbins, GA, Pierro, J, Selvaraj, S, Mezzano, V, Daves, M, Lupo, PJ, Scheurer, ME, Loomis, CA, Mullighan, CG, Chen, W, Rabin, KR, Tsirigos, A, Carroll, WL & Aifantis, I 2020, 'Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia', Cancer Cell, vol. 37, no. 6, pp. 867-882.e12. https://doi.org/10.1016/j.ccell.2020.04.015

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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 = "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",

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TY - JOUR

T1 - Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia

AU - Witkowski, Matthew T.

AU - Dolgalev, Igor

AU - Evensen, Nikki A.

AU - Ma, Chao

AU - Chambers, Tiffany

AU - Roberts, Kathryn G.

AU - Sreeram, Sheetal

AU - Dai, Yuling

AU - Tikhonova, Anastasia N.

AU - Lasry, Audrey

AU - Qu, Chunxu

AU - Pei, Deqing

AU - Cheng, Cheng

AU - Robbins, Gabriel A.

AU - Pierro, Joanna

AU - Selvaraj, Shanmugapriya

AU - Mezzano, Valeria

AU - Daves, Marla

AU - Lupo, Philip J.

AU - Scheurer, Michael E.

AU - Loomis, Cynthia A.

AU - Mullighan, Charles G.

AU - Chen, Weiqiang

AU - Rabin, Karen R.

AU - Tsirigos, Aristotelis

AU - Carroll, William L.

AU - Aifantis, Iannis

PY - 2020/6/8

Y1 - 2020/6/8

N2 - 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.

AB - 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.

KW - acute lymphoblastic leukemia

KW - chemotherapy

KW - immune microenvironment

KW - monocytes

KW - relapse

KW - single cell

KW - Prognosis

KW - Humans

KW - Child, Preschool

KW - Infant

KW - Male

KW - Case-Control Studies

KW - Young Adult

KW - Antineoplastic Agents/pharmacology

KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology

KW - Monocytes/immunology

KW - Tumor Microenvironment/immunology

KW - Bone Marrow Transplantation

KW - Adult

KW - Female

KW - Retrospective Studies

KW - Single-Cell Analysis

KW - Child

KW - Proteome/analysis

KW - Mice, Inbred C57BL

KW - Survival Rate

KW - Neoplasm Recurrence, Local/immunology

KW - Animals

KW - RNA-Seq

KW - Adolescent

UR - http://www.scopus.com/inward/record.url?scp=85085749879&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85085749879&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2020.04.015

DO - 10.1016/j.ccell.2020.04.015

M3 - Article

C2 - 32470390

AN - SCOPUS:85085749879

SN - 1535-6108

VL - 37

SP - 867-882.e12

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia

Abstract

Keywords

ASJC Scopus subject areas

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