An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

Ifat Geron; Angela Maria Savino; Hila Fishman; Noa Tal; John Brown; Virginia A. Turati; Chela James; Jolanda Sarno; Michal Hameiri-Grossman; Yu Nee Lee; Avigail Rein; Hillary Maniriho; Yehudit Birger; Anna Zemlyansky; Inna Muler; Kara L. Davis; Victoria Marcu-Malina; Nicole Mattson; Oren Parnas; Rabea Wagener; Ute Fischer; João T. Barata; Catriona H.M. Jamieson; Markus Müschen; Chun Wei Chen; Arndt Borkhardt; Ilan Richard Kirsch; Arnon Nagler; Tariq Enver; Shai Izraeli

doi:10.1038/s41467-022-28218-7

An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

Ifat Geron, Angela Maria Savino, Hila Fishman, Noa Tal, John Brown, Virginia A. Turati, Chela James, Jolanda Sarno, Michal Hameiri-Grossman, Yu Nee Lee, Avigail Rein, Hillary Maniriho, Yehudit Birger, Anna Zemlyansky, Inna Muler, Kara L. Davis, Victoria Marcu-Malina, Nicole Mattson, Oren Parnas, Rabea WagenerUte Fischer, João T. Barata, Catriona H.M. Jamieson, Markus Müschen, Chun Wei Chen, Arndt Borkhardt, Ilan Richard Kirsch, Arnon Nagler, Tariq Enver, Shai Izraeli^*

^*Corresponding author for this work

Department of Immunology and Cancer Research

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

9 Scopus citations

Abstract

Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis “ph-like” BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34⁺ hematopoietic stem and progenitor cells induces a preleukemic state in transplanted immunodeficient NOD/LtSz-scid IL2Rγ^null mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34⁺CD10^highCD19⁺ cells evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2 A (CDKN2A) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of CDKN2A in primary human CD34⁺ cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.

Original language	American English
Article number	659
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-28218-7
State	Published - Dec 2022

Bibliographical note

Funding Information:
We thank Michael Gershovits and Avital Sarusi-Portuguez from the Mantoux bioinformatics institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann institute of science, for RNAseq analysis service, Dvir Dahary for help with WGS data analysis and Idit Shiff from the Genomic Applications Laboratory, the Core Research Facility, Faculty of Medicine—Ein Kerem, the Hebrew University of Jerusalem, Israel, for 10X RNA sequencing services. We also thank Zhaohui Gu from COH for his assistance regarding PAX5 BCP-ALL subtypes. We are indebted to Nava Gershman, Alla Zozovsky, and Itzhak Ben Moshe for help with xenograft experiments. We thank the Rawlings lab for sharing the Eu-B29 lentiviral construct. Special thanks to Liron Tuval Kochen, Dafna Gaash, Hava Rosenfeld, and Keren Shichrur from the genetic laboratory of Schneider hospital for help in leukemic sample analysis. We thank all past and present members of S.I. research group for fruitful discussions and advice. This work was supported by the Israel Science Foundation (# 1178/12 to S.I.), Children with Cancer (UK) (S.I. and T.E.), Swiss Bridge Foundation (S.I.), WLBH Foundation (S.I.), Waxman Cancer Research Foundation (S.I.), US–Israel Binational Science Foundation, Israeli health ministry ERA-NET program (#CANCER11-FP-127 to S.I.), Hans Neufeld Stiftung, the International Collaboration Grant from the Jacki and Bruce Barron Cancer Research Scholars’ Program, a partnership of the Israel Cancer Research Fund and City of Hope (S.I. grants # 00161), the Nevzlin Genomic Center for Precision Medicine in Schneider Children’s Medical Center of Israel, The European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 813091 (S.I.) and the Israel Childhood Cancer Foundation (S.I.). I.G. was partially supported by Israeli ministry of Immigrant Absorption. This work was performed in partial fulfillment of the requirements for PhD degrees of Ifat Geron, Avigail Rein and Hillary Manriho, Sackler Faculty of Medicine, Tel Aviv University, Israel and of Ifat Geron in the Division of Biological Sciences University of California San Diego, USA.

Publisher Copyright:
© 2022, The Author(s).

Keywords

Animals
Antigens, CD34/genetics
Base Sequence
Cell Differentiation/genetics
Cyclin-Dependent Kinase Inhibitor p16/genetics
Gene Expression/immunology
Humans
Interleukin-7 Receptor alpha Subunit/genetics
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics
Precursor Cells, B-Lymphoid/immunology
RNA-Seq/methods
Receptors, Cytokine/genetics
Signal Transduction/genetics
Single-Cell Analysis/methods
Transplantation, Heterologous

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10.1038/s41467-022-28218-7

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Geron, I., Savino, A. M., Fishman, H., Tal, N., Brown, J., Turati, V. A., James, C., Sarno, J., Hameiri-Grossman, M., Lee, Y. N., Rein, A., Maniriho, H., Birger, Y., Zemlyansky, A., Muler, I., Davis, K. L., Marcu-Malina, V., Mattson, N., Parnas, O., ... Izraeli, S. (2022). An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia. Nature Communications, 13(1), Article 659. https://doi.org/10.1038/s41467-022-28218-7

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title = "An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia",

abstract = "Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis “ph-like” BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic stem and progenitor cells induces a preleukemic state in transplanted immunodeficient NOD/LtSz-scid IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2 A (CDKN2A) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.",

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author = "Ifat Geron and Savino, {Angela Maria} and Hila Fishman and Noa Tal and John Brown and Turati, {Virginia A.} and Chela James and Jolanda Sarno and Michal Hameiri-Grossman and Lee, {Yu Nee} and Avigail Rein and Hillary Maniriho and Yehudit Birger and Anna Zemlyansky and Inna Muler and Davis, {Kara L.} and Victoria Marcu-Malina and Nicole Mattson and Oren Parnas and Rabea Wagener and Ute Fischer and Barata, {Jo{\~a}o T.} and Jamieson, {Catriona H.M.} and Markus M{\"u}schen and Chen, {Chun Wei} and Arndt Borkhardt and Kirsch, {Ilan Richard} and Arnon Nagler and Tariq Enver and Shai Izraeli",

note = "Funding Information: We thank Michael Gershovits and Avital Sarusi-Portuguez from the Mantoux bioinformatics institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann institute of science, for RNAseq analysis service, Dvir Dahary for help with WGS data analysis and Idit Shiff from the Genomic Applications Laboratory, the Core Research Facility, Faculty of Medicine—Ein Kerem, the Hebrew University of Jerusalem, Israel, for 10X RNA sequencing services. We also thank Zhaohui Gu from COH for his assistance regarding PAX5 BCP-ALL subtypes. We are indebted to Nava Gershman, Alla Zozovsky, and Itzhak Ben Moshe for help with xenograft experiments. We thank the Rawlings lab for sharing the Eu-B29 lentiviral construct. Special thanks to Liron Tuval Kochen, Dafna Gaash, Hava Rosenfeld, and Keren Shichrur from the genetic laboratory of Schneider hospital for help in leukemic sample analysis. We thank all past and present members of S.I. research group for fruitful discussions and advice. This work was supported by the Israel Science Foundation (# 1178/12 to S.I.), Children with Cancer (UK) (S.I. and T.E.), Swiss Bridge Foundation (S.I.), WLBH Foundation (S.I.), Waxman Cancer Research Foundation (S.I.), US–Israel Binational Science Foundation, Israeli health ministry ERA-NET program (#CANCER11-FP-127 to S.I.), Hans Neufeld Stiftung, the International Collaboration Grant from the Jacki and Bruce Barron Cancer Research Scholars{\textquoteright} Program, a partnership of the Israel Cancer Research Fund and City of Hope (S.I. grants # 00161), the Nevzlin Genomic Center for Precision Medicine in Schneider Children{\textquoteright}s Medical Center of Israel, The European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska-Curie grant agreement No 813091 (S.I.) and the Israel Childhood Cancer Foundation (S.I.). I.G. was partially supported by Israeli ministry of Immigrant Absorption. This work was performed in partial fulfillment of the requirements for PhD degrees of Ifat Geron, Avigail Rein and Hillary Manriho, Sackler Faculty of Medicine, Tel Aviv University, Israel and of Ifat Geron in the Division of Biological Sciences University of California San Diego, USA. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-28218-7",

language = "American English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

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Geron, I, Savino, AM, Fishman, H, Tal, N, Brown, J, Turati, VA, James, C, Sarno, J, Hameiri-Grossman, M, Lee, YN, Rein, A, Maniriho, H, Birger, Y, Zemlyansky, A, Muler, I, Davis, KL, Marcu-Malina, V, Mattson, N, Parnas, O, Wagener, R, Fischer, U, Barata, JT, Jamieson, CHM, Müschen, M, Chen, CW, Borkhardt, A, Kirsch, IR, Nagler, A, Enver, T & Izraeli, S 2022, 'An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia', Nature Communications, vol. 13, no. 1, 659. https://doi.org/10.1038/s41467-022-28218-7

TY - JOUR

T1 - An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

AU - Geron, Ifat

AU - Savino, Angela Maria

AU - Fishman, Hila

AU - Tal, Noa

AU - Brown, John

AU - Turati, Virginia A.

AU - James, Chela

AU - Sarno, Jolanda

AU - Hameiri-Grossman, Michal

AU - Lee, Yu Nee

AU - Rein, Avigail

AU - Maniriho, Hillary

AU - Birger, Yehudit

AU - Zemlyansky, Anna

AU - Muler, Inna

AU - Davis, Kara L.

AU - Marcu-Malina, Victoria

AU - Mattson, Nicole

AU - Parnas, Oren

AU - Wagener, Rabea

AU - Fischer, Ute

AU - Barata, João T.

AU - Jamieson, Catriona H.M.

AU - Müschen, Markus

AU - Chen, Chun Wei

AU - Borkhardt, Arndt

AU - Kirsch, Ilan Richard

AU - Nagler, Arnon

AU - Enver, Tariq

AU - Izraeli, Shai

N1 - Funding Information: We thank Michael Gershovits and Avital Sarusi-Portuguez from the Mantoux bioinformatics institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann institute of science, for RNAseq analysis service, Dvir Dahary for help with WGS data analysis and Idit Shiff from the Genomic Applications Laboratory, the Core Research Facility, Faculty of Medicine—Ein Kerem, the Hebrew University of Jerusalem, Israel, for 10X RNA sequencing services. We also thank Zhaohui Gu from COH for his assistance regarding PAX5 BCP-ALL subtypes. We are indebted to Nava Gershman, Alla Zozovsky, and Itzhak Ben Moshe for help with xenograft experiments. We thank the Rawlings lab for sharing the Eu-B29 lentiviral construct. Special thanks to Liron Tuval Kochen, Dafna Gaash, Hava Rosenfeld, and Keren Shichrur from the genetic laboratory of Schneider hospital for help in leukemic sample analysis. We thank all past and present members of S.I. research group for fruitful discussions and advice. This work was supported by the Israel Science Foundation (# 1178/12 to S.I.), Children with Cancer (UK) (S.I. and T.E.), Swiss Bridge Foundation (S.I.), WLBH Foundation (S.I.), Waxman Cancer Research Foundation (S.I.), US–Israel Binational Science Foundation, Israeli health ministry ERA-NET program (#CANCER11-FP-127 to S.I.), Hans Neufeld Stiftung, the International Collaboration Grant from the Jacki and Bruce Barron Cancer Research Scholars’ Program, a partnership of the Israel Cancer Research Fund and City of Hope (S.I. grants # 00161), the Nevzlin Genomic Center for Precision Medicine in Schneider Children’s Medical Center of Israel, The European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 813091 (S.I.) and the Israel Childhood Cancer Foundation (S.I.). I.G. was partially supported by Israeli ministry of Immigrant Absorption. This work was performed in partial fulfillment of the requirements for PhD degrees of Ifat Geron, Avigail Rein and Hillary Manriho, Sackler Faculty of Medicine, Tel Aviv University, Israel and of Ifat Geron in the Division of Biological Sciences University of California San Diego, USA. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis “ph-like” BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic stem and progenitor cells induces a preleukemic state in transplanted immunodeficient NOD/LtSz-scid IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2 A (CDKN2A) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.

AB - Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis “ph-like” BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic stem and progenitor cells induces a preleukemic state in transplanted immunodeficient NOD/LtSz-scid IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2 A (CDKN2A) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.

KW - Animals

KW - Antigens, CD34/genetics

KW - Base Sequence

KW - Cell Differentiation/genetics

KW - Cyclin-Dependent Kinase Inhibitor p16/genetics

KW - Gene Expression/immunology

KW - Humans

KW - Interleukin-7 Receptor alpha Subunit/genetics

KW - Mice, Inbred NOD

KW - Mice, Knockout

KW - Mice, SCID

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

KW - Precursor Cells, B-Lymphoid/immunology

KW - RNA-Seq/methods

KW - Receptors, Cytokine/genetics

KW - Signal Transduction/genetics

KW - Single-Cell Analysis/methods

KW - Transplantation, Heterologous

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U2 - 10.1038/s41467-022-28218-7

DO - 10.1038/s41467-022-28218-7

M3 - Article

C2 - 35115489

AN - SCOPUS:85123974510

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 659

ER -

An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

Abstract

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Keywords

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