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Panobinostat (LBH589) increase survival in adult xenografic model of acute lymphoblastic leukemia with t(4;11) but promotes antagonistic effects in combination with MTX and 6MP

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Abstract

Patients diagnosed with acute lymphoblastic leukemia (ALL) bearing t(4;11)/MLL-AF4 have aggressive clinical features, poor prognosis and there is an urgent need for new therapies to improve outcomes. Panobinostat (LBH589) has been identified as a potential therapeutic agent for ALL with t(4;11) and studies suggest that the antineoplastic effects are associated with reduced MLL-AF4 fusion protein and reduced expression of HOX genes. Here, we evaluated the in vitro effects of the combination of LBH589 with methotrexate (MTX) or 6-mercaptopurine (6MP) by cell proliferation assays and Calcusyn software in ALL cell line (RS4;11); the in vivo effects of LBH589 in xenotransplanted NOD-scid IL2Rgammanull mice measuring human lymphoblasts by flow cytometry; and the expression of HOX genes by qPCR after treatment in an adult model of ALL with t(4;11). LBH589 combination with MTX or 6MP did not promote synergistic effects in RS4;11 cell line. LBH589 treatment leads to increased overall survival and reduction of blasts in xenotransplanted mice but caused no significant changes in HOXA7, HOXA9, HOXA10, and MEIS1 expression. The LBH589, alone, showed promising antineoplastic effects in vivo and may represent a potential agent for chemotherapy in ALL patients with t(4;11).

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Acknowledgements

We thank Priscila Santos Scheucher, Hemocentro, Medical School of Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil, Ribeirão Preto, Brazil, for assistance in flow cytometry, Rosane Gomes de Paula Queiroz and Veridiana Kiill Suazo, Medical School of Ribeirão Preto, for technical support and Dr. Davi Casele Aragon, statistic of Pediatric Department of Medical School of Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil.

Funding

Conselho Nacional de Pesquisa (CNPq) and Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP), process number 2012/18383-0.

Author information

Author notes

  1. Luiz Gonzaga Tone

    Present address: Pediatrics Department of Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

Authors and Affiliations

  1. Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, São Paulo, CEP 14784 400, Brazil

    Daniel Antunes Moreno & Howard Lopes Ribeiro Junior

  2. Boldrini Child Center, Campinas, SP, Brazil

    Angelo Brunelli Albertoni Laranjeira & José Andres Yunes

  3. Pediatrics Department of Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Gustavo Alencastro Veiga Cruzeiro & Carlos Alberto Scrideli

  4. Genetics Department of Medical School of Ribeirão Preto, Ribeirão Preto, SP, Brazil

    Kleiton Silva Borges & Karina Bezerra Salomão

  5. Pathology Department of Medical School of Ribeirão Preto, Ribeirão Preto, SP, Brazil

    Fernando Silva Ramalho

  6. Hemocentro Foundation of Ribeirão Preto, Ribeirão Preto, SP, Brazil

    Cleide Lúcia Araújo Silva & Eduardo Magalhães Rego

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Moreno, D.A., Junior, H.L.R., Laranjeira, A.B.A. et al. Panobinostat (LBH589) increase survival in adult xenografic model of acute lymphoblastic leukemia with t(4;11) but promotes antagonistic effects in combination with MTX and 6MP. Med Oncol 39, 216 (2022). https://doi.org/10.1007/s12032-022-01813-w

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