Leveraging IFNγ/CD38 regulation to unmask and target leukemia stem cells in acute myelogenous leukemia.

التفاصيل البيبلوغرافية
العنوان: Leveraging IFNγ/CD38 regulation to unmask and target leukemia stem cells in acute myelogenous leukemia.
المؤلفون: Murtadha M; Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; Duarte, CA, USA.; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA., Park M; Department of Molecular Medicine, Beckman Research Institute, City of Hope; Duarte, CA, USA., Zhu Y; Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; Duarte, CA, USA.; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA., Caserta E; Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; Duarte, CA, USA.; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA., Dona AA; Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; Duarte, CA, USA.; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA., Singer M; Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; Duarte, CA, USA.; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA., Vahed H; Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; Duarte, CA, USA.; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA., Tasndoh T; Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; Duarte, CA, USA.; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA., Gonzalez A; Department of Molecular Medicine, Beckman Research Institute, City of Hope; Duarte, CA, USA., Ly K; Department of Molecular Medicine, Beckman Research Institute, City of Hope; Duarte, CA, USA., Sanchez JF; Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; Duarte, CA, USA., Chowdhury A; Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; Duarte, CA, USA.; Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope; Duarte, CA, USA., Pozhitkov A; Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; Duarte, CA, USA.; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA., Ghoda L; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA., Li L; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA., Zhang B; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA., Krishnan A; Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; Duarte, CA, USA., Marcucci G; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA., Williams J; Department of Molecular Medicine, Beckman Research Institute, City of Hope; Duarte, CA, USA., Pichiorri F; Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; Duarte, CA, USA.; Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA.
المصدر: BioRxiv : the preprint server for biology [bioRxiv] 2023 Mar 01. Date of Electronic Publication: 2023 Mar 01.
نوع المنشور: Preprint
اللغة: English
بيانات الدورية: Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
مستخلص: Elimination of drug-resistant leukemia stem cells (LSCs) represents a major challenge to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38 pos ), the presence of CD34 and lack of CD38 expression (CD34 pos CD38 neg ) are immunophenotypic features of both LSC-enriched AML blasts and normal hematopoietic stem cells (HSCs). We report that IFN-γ induces CD38 upregulation in LSC-enriched CD34 pos CD38 neg AML blasts, but not in CD34 pos CD38 neg HSCs. To leverage the IFN-γ mediated CD38 up-regulation in LSCs for clinical application, we created a compact, single-chain CD38-CD3-T cell engager (CD38-BIONIC) able to direct T cells against CD38 pos blasts. Activated CD4 pos and CD8 pos T cells not only kill AML blasts but also produce IFNγ, which leads to CD38 expression on CD34 pos CD38 neg LSC-enriched blasts. These cells then become CD38-BIONIC targets. The net result is an immune-mediated killing of both CD38 neg and CD38 pos AML blasts, which culminates in LSC depletion.
Competing Interests: Conflict of interest: The authors declare no relevant conflicts of interest.
معلومات مُعتمدة: R50 CA252135 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: CD38; acute myeloid leukemia; bispecific T cell engagers; interferon gamma; leukemia stem cells
تواريخ الأحداث: Date Created: 20230313 Latest Revision: 20231019
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10002674
DOI: 10.1101/2023.02.27.530273
PMID: 36909542
قاعدة البيانات: MEDLINE
الوصف
DOI:10.1101/2023.02.27.530273