Development of combination therapies with BTK inhibitors and dasatinib to treat CNS-infiltrating E2A-PBX1+/preBCR+ ALL.

Autor:	Gentile G; Department of Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Poggio T; Department of Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Catalano A; Department of Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Voutilainen M; Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland., Lahnalampi M; Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland., Andrade-Martinez M; Department of Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Ma T; Department of Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Sankowski R; Department of Neuropathology, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Goncharenko L; Institute for Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Proteomics Platform - Core Facility, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Tholen S; Institute of Surgical Pathology, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Proteomics Platform - Core Facility, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Han K; Department of Genetics, Stanford University School of Medicine, Stanford, CA., Morgens DW; Department of Genetics, Stanford University School of Medicine, Stanford, CA., Prinz M; Department of Neuropathology, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Signaling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany., Lübbert M; Department of Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Engel S; Department of Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Hartmann TN; Department of Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Cario G; Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany., Schrappe M; Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany., Lenk L; Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany., Stanulla M; Department of Pediatrics, University Medical Center Hannover, Hannover, Germany., Duyster J; Department of Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Bronsert P; Institute of Surgical Pathology, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Bassik MC; Department of Genetics, Stanford University School of Medicine, Stanford, CA., Cleary ML; Department of Pathology, Stanford University School of Medicine, Stanford, CA., Schilling O; Institute for Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Proteomics Platform - Core Facility, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Heinäniemi M; Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland., Duque-Afonso J; Department of Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 Jun 11; Vol. 8 (11), pp. 2846-2860.
DOI:	10.1182/bloodadvances.2023011582
Abstrakt:	Abstract: The t(1;19) translocation, encoding the oncogenic fusion protein E2A (TCF3)-PBX1, is involved in acute lymphoblastic leukemia (ALL) and associated with a pre-B-cell receptor (preBCR+) phenotype. Relapse in patients with E2A-PBX1+ ALL frequently occurs in the central nervous system (CNS). Therefore, there is a medical need for the identification of CNS active regimens for the treatment of E2A-PBX1+/preBCR+ ALL. Using unbiased short hairpin RNA (shRNA) library screening approaches, we identified Bruton tyrosine kinase (BTK) as a key gene involved in both proliferation and dasatinib sensitivity of E2A-PBX1+/preBCR+ ALL. Depletion of BTK by shRNAs resulted in decreased proliferation of dasatinib-treated E2A-PBX1+/preBCR+ cells compared with control-transduced cells. Moreover, the combination of dasatinib with BTK inhibitors (BTKi; ibrutinib, acalabrutinib, or zanubrutinib) significantly decreased E2A-PBX1+/preBCR+ human and murine cell proliferation, reduced phospholipase C gamma 2 (PLCG2) and BTK phosphorylation and total protein levels and increased disease-free survival of mice in secondary transplantation assays, particularly reducing CNS-leukemic infiltration. Hence, dasatinib with ibrutinib reduced pPLCG2 and pBTK in primary ALL patient samples, including E2A-PBX1+ ALLs. In summary, genetic depletion and pharmacological inhibition of BTK increase dasatinib effects in human and mouse with E2A-PBX1+/preBCR+ ALL across most of performed assays, with the combination of dasatinib and BTKi proving effective in reducing CNS infiltration of E2A-PBX1+/preBCR+ ALL cells in vivo. (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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