PMID- 31530562 OWN - NLM STAT- MEDLINE DCOM- 20200330 LR - 20210202 IS - 1528-0020 (Electronic) IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 134 IP - 24 DP - 2019 Dec 12 TI - IL-7R is essential for leukemia-initiating cell activity of T-cell acute lymphoblastic leukemia. PG - 2171-2182 LID - 10.1182/blood.2019000982 [doi] AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy resulting from the dysregulation of signaling pathways that control intrathymic T-cell development. Relapse rates are still significant, and prognosis is particularly bleak for relapsed patients. Therefore, development of novel therapies specifically targeting pathways controlling leukemia-initiating cell (LIC) activity is mandatory for fighting refractory T-ALL. The interleukin-7 receptor (IL-7R) is a crucial T-cell developmental pathway that is commonly expressed in T-ALL and has been implicated in leukemia progression; however, the significance of IL-7R/IL-7 signaling in T-ALL pathogenesis and its contribution to disease relapse remain unknown. To directly explore whether IL-7R targeting may be therapeutically efficient against T-ALL relapse, we focused on a known Notch1-induced T-ALL model, because a majority of T-ALL patients harbor activating mutations in NOTCH1, which is a transcriptional regulator of IL-7R expression. Using loss-of-function approaches, we show that Il7r-deficient, but not wild-type, mouse hematopoietic progenitors transduced with constitutively active Notch1 failed to generate leukemia upon transplantation into immunodeficient mice, thus providing formal evidence that IL-7R function is essential for Notch1-induced T-cell leukemogenesis. Moreover, we demonstrate that IL-7R expression is an early functional biomarker of T-ALL cells with LIC potential and report that impaired IL-7R signaling hampers engraftment and progression of patient-derived T-ALL xenografts. Notably, we show that IL-7R-dependent LIC activity and leukemia progression can be extended to human B-cell acute lymphoblastic leukemia (B-ALL). These results have important therapeutic implications, highlighting the relevance that targeting normal IL-7R signaling may have in future therapeutic interventions, particularly for preventing T-ALL (and B-ALL) relapse. CI - (c) 2019 by The American Society of Hematology. FAU - Gonzalez-Garcia, Sara AU - Gonzalez-Garcia S AD - Department of Cell Biology and Immunology, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas-Universidad Autonoma de Madrid (CSIC-UAM), Madrid, Spain. FAU - Mosquera, Marta AU - Mosquera M AD - Department of Cell Biology and Immunology, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas-Universidad Autonoma de Madrid (CSIC-UAM), Madrid, Spain. FAU - Fuentes, Patricia AU - Fuentes P AD - Department of Cell Biology and Immunology, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas-Universidad Autonoma de Madrid (CSIC-UAM), Madrid, Spain. FAU - Palumbo, Tiziana AU - Palumbo T AD - Department of Cell Biology and Immunology, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas-Universidad Autonoma de Madrid (CSIC-UAM), Madrid, Spain. FAU - Escudero, Adela AU - Escudero A AD - Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, Instituto de Genetica Medica y Molecular del Instituto de Investigacion Sanitaria del Hospital Universitario La Paz (INGEMM-IdiPAZ), Madrid, Spain. FAU - Perez-Martinez, Antonio AU - Perez-Martinez A AD - Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, Instituto de Genetica Medica y Molecular del Instituto de Investigacion Sanitaria del Hospital Universitario La Paz (INGEMM-IdiPAZ), Madrid, Spain. AD - Pediatric Hemato-Oncology Service, Hospital Universitario La Paz, Madrid, Spain. AD - Department of Pediatrics, UAM, Madrid, Spain. FAU - Ramirez, Manuel AU - Ramirez M AD - Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Nino Jesus, UAM, Spain and. FAU - Corcoran, Anne E AU - Corcoran AE AD - Nuclear Dynamics Programme and Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom. FAU - Toribio, Maria L AU - Toribio ML AD - Department of Cell Biology and Immunology, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas-Universidad Autonoma de Madrid (CSIC-UAM), Madrid, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Antineoplastic Agents, Immunological) RN - 0 (Biomarkers) RN - 0 (Receptor, Notch1) RN - 0 (Receptors, Interleukin-7) SB - IM MH - Animals MH - Antineoplastic Agents, Immunological/pharmacology/therapeutic use MH - Biomarkers MH - Cell Line, Tumor MH - Disease Models, Animal MH - *Disease Susceptibility MH - Gene Expression MH - Hematopoietic Stem Cells/metabolism MH - Humans MH - Mice MH - Neoplastic Stem Cells/*metabolism/pathology MH - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*etiology/*metabolism/pathology MH - Receptor, Notch1/genetics/metabolism MH - Receptors, Interleukin-7/genetics/*metabolism MH - Signal Transduction/drug effects MH - Xenograft Model Antitumor Assays PMC - PMC6933515 COIS- Conflict-of-interest disclosures: The authors declare no competing financial interests. EDAT- 2019/09/19 06:00 MHDA- 2020/03/31 06:00 PMCR- 2019/12/12 CRDT- 2019/09/19 06:00 PHST- 2019/04/05 00:00 [received] PHST- 2019/09/05 00:00 [accepted] PHST- 2019/09/19 06:00 [pubmed] PHST- 2020/03/31 06:00 [medline] PHST- 2019/09/19 06:00 [entrez] PHST- 2019/12/12 00:00 [pmc-release] AID - S0006-4971(20)73148-4 [pii] AID - 2019/BLD2019000982 [pii] AID - 10.1182/blood.2019000982 [doi] PST - ppublish SO - Blood. 2019 Dec 12;134(24):2171-2182. doi: 10.1182/blood.2019000982.