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.

Geron, I., Savino, A., Fishman, H., Tal, N., Brown, J., Turati, V., et al. (2022). An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia. NATURE COMMUNICATIONS, 13 [10.1038/s41467-022-28218-7].

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

Savino, Angela Maria
Co-primo
;
Sarno, Jolanda;
2022

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.
Si
Articolo in rivista - Articolo scientifico
Scientifica
Animals; Antigens, CD34; Base Sequence; Cell Differentiation; Cyclin-Dependent Kinase Inhibitor p16; Gene Expression; Humans; Interleukin-7 Receptor alpha Subunit; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cells, B-Lymphoid; RNA-Seq; Receptors, Cytokine; Signal Transduction; Single-Cell Analysis; Transplantation, Heterologous
English
Geron, I., Savino, A., Fishman, H., Tal, N., Brown, J., Turati, V., et al. (2022). An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia. NATURE COMMUNICATIONS, 13 [10.1038/s41467-022-28218-7].
Geron, I; Savino, A; Fishman, H; Tal, N; Brown, J; Turati, V; James, C; Sarno, J; Hameiri-Grossman, M; Lee, Y; Rein, A; Maniriho, H; Birger, Y; Zemlyansky, A; Muler, I; Davis, K; Marcu-Malina, V; Mattson, N; Parnas, O; Wagener, R; Fischer, U; Barata, J; Jamieson, C; Müschen, M; Chen, C; Borkhardt, A; Kirsch, I; Nagler, A; Enver, T; Izraeli, S
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/391256
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