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

Nat Commun. 2022 Feb 3;13(1):659. doi: 10.1038/s41467-022-28218-7.

Authors

Ifat Geron^#^{1

2

3}, Angela Maria Savino^#^{1

2

3}, Hila Fishman^{1

2

3}, Noa Tal^{1

2}, John Brown⁴, Virginia A Turati⁴, Chela James⁴, Jolanda Sarno⁵, Michal Hameiri-Grossman³, Yu Nee Lee^{1

6}, Avigail Rein^{1

2

3}, Hillary Maniriho^{1

3}, Yehudit Birger^{1

2

3}, Anna Zemlyansky³, Inna Muler², Kara L Davis⁵, Victoria Marcu-Malina⁷, Nicole Mattson⁸, Oren Parnas⁹, Rabea Wagener¹⁰, Ute Fischer¹⁰, João T Barata¹¹, Catriona H M Jamieson¹², Markus Müschen⁸, Chun-Wei Chen⁸, Arndt Borkhardt¹⁰, Ilan Richard Kirsch¹³, Arnon Nagler^{1

14}, Tariq Enver⁴, Shai Izraeli^{15

16

17

18}

Affiliations

¹ Felsenstein Medical Research Center and The Molecular Genetics and Biochemistry Department, Sackler Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel.
² Institute of Pediatric Research, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel Hashomer, Israel.
³ The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
⁴ Department of Cancer Biology, UCL Cancer Institute, UCL, London, UK.
⁵ Department of Pediatrics, Bass Center for Childhood Cancer and Blood Disorders, Stanford University, Stanford, CA, USA.
⁶ Pediatric Department and the Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital Sheba Medical Center, Tel-Hashomer, Israel.
⁷ Cytogenetic Unit laboratory of Hematology, Chaim Sheba Medical Center Tel Hashomer, Tel Hashomer, Israel.
⁸ Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA, USA.
⁹ The Concern Foundation Laboratories at the Lautenberg Center for immunology and Cancer Research, IMRIC, Hebrew University Faculty of Medicine, Jerusalem, Israel.
¹⁰ Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
¹¹ Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
¹² UC San Diego, Moores Cancer Center, Division of Regenerative Medicine, Department of Medicine and Sanford Stem Cell Clinical Center, Ja Jolla, CA, USA.
¹³ Adaptive Biotechnologies, Inc., Seattle, WA, USA.
¹⁴ Hematology Division BMT and Cord Blood Bank Chaim Sheba Medical Center Tel-Hashomer, Tel-Hashomer, Israel.
¹⁵ Felsenstein Medical Research Center and The Molecular Genetics and Biochemistry Department, Sackler Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel. sizraeli@gmail.com.
¹⁶ Institute of Pediatric Research, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel Hashomer, Israel. sizraeli@gmail.com.
¹⁷ The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children's Medical Center of Israel, Petach Tikva, Israel. sizraeli@gmail.com.
¹⁸ Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA, USA. sizraeli@gmail.com.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

Antigens, CD34
CRLF2 protein, human
Cyclin-Dependent Kinase Inhibitor p16
Interleukin-7 Receptor alpha Subunit
Receptors, Cytokine

Abstract

Publication types

MeSH terms

Substances

Grants and funding