PMID- 34193976 OWN - NLM STAT- MEDLINE DCOM- 20220218 LR - 20240405 IS - 1476-5551 (Electronic) IS - 0887-6924 (Print) IS - 0887-6924 (Linking) VI - 36 IP - 1 DP - 2022 Jan TI - Activated interleukin-7 receptor signaling drives B-cell acute lymphoblastic leukemia in mice. PG - 42-57 LID - 10.1038/s41375-021-01326-x [doi] AB - Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-ALL often associated with genetic variants that alter cytokine receptor signaling, including mutations in the interleukin-7 receptor (IL7R). To investigate whether IL7R variants are leukemia-initiating, we built mouse models expressing activated Il7r (aIL7R). B-cell intrinsic aIL7R mice developed spontaneous B-ALL, demonstrating sufficiency of Il7r activating mutations in leukemogenesis. Concomitant introduction of a knock-out allele in the associated adapter protein Lnk (encoded by Sh2b3) or a dominant-negative variant of the transcription factor Ikaros (Ikzf1) increased disease penetrance. The resulting murine leukemias displayed monoclonality and recurrent somatic Kras mutations and efficiently engrafted into immunocompetent mice. Phosphoproteomic analyses of aIL7R leukemic cells revealed constitutive Stat5 signaling and B cell receptor (BCR)-like signaling despite the absence of surface pre-BCR. Finally, in vitro treatment of aIL7R leukemic B-cells with Jak, mTOR, or Syk inhibitors blocked growth, confirming that each pathway is active in this mouse model of IL7R-driven B-ALL. CI - (c) 2021. The Author(s), under exclusive licence to Springer Nature Limited. FAU - Thomas, Kerri R AU - Thomas KR AD - Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA. AD - Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA. FAU - Allenspach, Eric J AU - Allenspach EJ AUID- ORCID: 0000-0001-7346-5835 AD - Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA. AD - Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. AD - Brotman-Baty Institute for Precision Medicine, Seattle, WA, USA. FAU - Camp, Nathan D AU - Camp ND AD - Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA. FAU - Wray-Dutra, Michelle N AU - Wray-Dutra MN AD - Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA. FAU - Khim, Socheath AU - Khim S AD - Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA. FAU - Zielinska-Kwiatkowska, Anna AU - Zielinska-Kwiatkowska A AD - Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA. FAU - Timms, Andrew E AU - Timms AE AD - Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA. FAU - Loftus, Joseph P AU - Loftus JP AD - Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. AD - Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA. FAU - Liggitt, H Denny AU - Liggitt HD AD - Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA, USA. FAU - Georgopoulos, Katia AU - Georgopoulos K AUID- ORCID: 0000-0002-8963-4258 AD - Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. FAU - Tasian, Sarah K AU - Tasian SK AUID- ORCID: 0000-0003-1327-1662 AD - Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. AD - Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA. AD - Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. AD - Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. FAU - James, Richard G AU - James RG AUID- ORCID: 0000-0002-2302-7367 AD - Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA. rickerj@uw.edu. AD - Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. rickerj@uw.edu. AD - Brotman-Baty Institute for Precision Medicine, Seattle, WA, USA. rickerj@uw.edu. AD - Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, USA. rickerj@uw.edu. FAU - Rawlings, David J AU - Rawlings DJ AUID- ORCID: 0000-0002-0810-1776 AD - Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA. drawling@uw.edu. AD - Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA. drawling@uw.edu. AD - Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. drawling@uw.edu. LA - eng GR - U01 CA243072/CA/NCI NIH HHS/United States GR - TL1 TR000422/TR/NCATS NIH HHS/United States GR - U01 CA232486/CA/NCI NIH HHS/United States GR - K08 CA184418/CA/NCI NIH HHS/United States GR - R01 CA201135/CA/NCI NIH HHS/United States GR - DP3 DK111802/DK/NIDDK NIH HHS/United States GR - K08 DK114568/DK/NIDDK NIH HHS/United States GR - TL1 TR002318/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20210630 PL - England TA - Leukemia JT - Leukemia JID - 8704895 RN - 0 (Receptors, Interleukin-7) SB - IM MH - Animals MH - Apoptosis MH - Cell Proliferation MH - *Gene Expression Regulation, Leukemic MH - Humans MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/etiology/metabolism/*pathology MH - Receptors, Interleukin-7/genetics/*metabolism MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays PMC - PMC8716641 MID - NIHMS1721181 EDAT- 2021/07/02 06:00 MHDA- 2022/02/19 06:00 PMCR- 2022/01/06 CRDT- 2021/07/01 06:48 PHST- 2021/01/21 00:00 [received] PHST- 2021/06/11 00:00 [accepted] PHST- 2021/06/09 00:00 [revised] PHST- 2021/07/02 06:00 [pubmed] PHST- 2022/02/19 06:00 [medline] PHST- 2021/07/01 06:48 [entrez] PHST- 2022/01/06 00:00 [pmc-release] AID - 10.1038/s41375-021-01326-x [pii] AID - 10.1038/s41375-021-01326-x [doi] PST - ppublish SO - Leukemia. 2022 Jan;36(1):42-57. doi: 10.1038/s41375-021-01326-x. Epub 2021 Jun 30.