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 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/2/3
Y1 - 2022/2/3
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.
UR - https://www.scopus.com/pages/publications/85123974510
U2 - 10.1038/s41467-022-28218-7
DO - 10.1038/s41467-022-28218-7
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C2 - 35115489
AN - SCOPUS:85123974510
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 659
ER -
