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Geron, Ifat; Savino, Angela Maria; Fishman, Hila; Tal, Noa; Brown, John; Turati, Virginia A.; James, Chela; Sarno, Jolanda; Hameiri-Grossman, Michal; Lee, Yu Nee; Rein, Avigail; Maniriho, Hillary; Birger, Yehudit; Zemlyansky, Anna; Muler, Inna; Davis, Kara L.; Marcu-Malina, Victoria; Mattson, Nicole; Parnas, Oren; Wagener, Rabea; Fischer, Ute; Barata, João T.; Jamieson, Catriona H. M.; Müschen, Markus; [...]

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

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  • Medientyp: E-Artikel
  • Titel: An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia
  • Beteiligte: Geron, Ifat; Savino, Angela Maria; Fishman, Hila; Tal, Noa; Brown, John; Turati, Virginia A.; James, Chela; Sarno, Jolanda; Hameiri-Grossman, Michal; Lee, Yu Nee; Rein, Avigail; Maniriho, Hillary; Birger, Yehudit; Zemlyansky, Anna; Muler, Inna; Davis, Kara L.; Marcu-Malina, Victoria; Mattson, Nicole; Parnas, Oren; Wagener, Rabea; Fischer, Ute; Barata, João T.; Jamieson, Catriona H. M.; Müschen, Markus; [...]
  • Erschienen: Springer Science and Business Media LLC, 2022
  • Erschienen in: Nature Communications
  • Sprache: Englisch
  • DOI: 10.1038/s41467-022-28218-7
  • ISSN: 2041-1723
  • Schlagwörter: General Physics and Astronomy ; General Biochemistry, Genetics and Molecular Biology ; General Chemistry ; Multidisciplinary
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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<jats:sup>+</jats:sup>hematopoietic stem and progenitor cells induces a preleukemic state in transplanted immunodeficient NOD/LtSz-<jats:italic>scid IL2Rγ</jats:italic><jats:sup><jats:italic>null</jats:italic></jats:sup>mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34<jats:sup>+</jats:sup>CD10<jats:sup>high</jats:sup>CD19<jats:sup>+</jats:sup>cells evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2 A (<jats:italic>CDKN2A</jats:italic>) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of<jats:italic>CDKN2A</jats:italic>in primary human CD34<jats:sup>+</jats:sup>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.</jats:p>
  • Zugangsstatus: Freier Zugang