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 and Shai Izraeli ()
Additional contact information
Ifat Geron: Tel Aviv University
Angela Maria Savino: Tel Aviv University
Hila Fishman: Tel Aviv University
Noa Tal: Tel Aviv University
John Brown: UCL Cancer Institute, UCL
Virginia A. Turati: UCL Cancer Institute, UCL
Chela James: UCL Cancer Institute, UCL
Jolanda Sarno: Stanford University
Michal Hameiri-Grossman: The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children’s Medical Center of Israel
Yu Nee Lee: Tel Aviv University
Avigail Rein: Tel Aviv University
Hillary Maniriho: Tel Aviv University
Yehudit Birger: Tel Aviv University
Anna Zemlyansky: The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children’s Medical Center of Israel
Inna Muler: Chaim Sheba Medical Center
Kara L. Davis: Stanford University
Victoria Marcu-Malina: Chaim Sheba Medical Center Tel Hashomer
Nicole Mattson: City of Hope Comprehensive Cancer Center
Oren Parnas: Hebrew University Faculty of Medicine
Rabea Wagener: Heinrich-Heine-University Düsseldorf
Ute Fischer: Heinrich-Heine-University Düsseldorf
João T. Barata: Universidade de Lisboa
Catriona H. M. Jamieson: Department of Medicine and Sanford Stem Cell Clinical Center
Markus Müschen: City of Hope Comprehensive Cancer Center
Chun-Wei Chen: City of Hope Comprehensive Cancer Center
Arndt Borkhardt: Heinrich-Heine-University Düsseldorf
Ilan Richard Kirsch: Adaptive Biotechnologies, Inc.
Arnon Nagler: Tel Aviv University
Tariq Enver: UCL Cancer Institute, UCL
Shai Izraeli: Tel Aviv University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-28218-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28218-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-28218-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().