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Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia.
Eldfors, S; Kuusanmäki, H; Kontro, M; Majumder, M M; Parsons, A; Edgren, H; Pemovska, T; Kallioniemi, O; Wennerberg, K; Gökbuget, N; Burmeister, T; Porkka, K; Heckman, C A.
Afiliación
  • Eldfors S; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Kuusanmäki H; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Kontro M; Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland.
  • Majumder MM; Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland.
  • Parsons A; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Edgren H; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Pemovska T; MediSapiens Ltd., Helsinki, Finland.
  • Kallioniemi O; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Wennerberg K; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Gökbuget N; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Burmeister T; Department of Medicine II, Goethe University, Frankfurt, Germany.
  • Porkka K; Charité Universtätsmedizin Berlin, Med. Klinik für Hämatologie, Onkologie und Tumorimmunologie, Berlin, Germany.
  • Heckman CA; Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland.
Leukemia ; 31(1): 51-57, 2017 01.
Article en En | MEDLINE | ID: mdl-27461063
TCF3-PBX1 (E2A-PBX1) is a recurrent gene fusion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), which is caused by the translocation t(1;19)(q23;p13). TCF3-PBX1 BCP-ALL patients typically benefit from chemotherapy; however, many relapse and subsequently develop resistant disease with few effective treatment options. Mechanisms driving disease progression and therapy resistance have not been studied in TCF3-PBX1 BCP-ALL. Here, we aimed to identify novel treatment options for TCF3-PBX1 BCP-ALL by profiling leukemia cells from a relapsed patient, and determine molecular mechanisms underlying disease pathogenesis and progression. By drug-sensitivity testing of leukemic blasts from the index patient, control samples and TCF3-PBX1 positive and negative BCP-ALL cell lines, we identified the phosphatidylinositide 3-kinase delta (p110δ) inhibitor idelalisib as an effective treatment for TCF3-PBX1 BCP-ALL. This was further supported by evidence showing TCF3-PBX1 directly regulates expression of PIK3CD, the gene encoding p110δ. Other somatic mutations to TP53 and MTOR, as well as aberrant expression of CXCR4, may influence additional drug sensitivities specific to the index patient and accompanied progression of the disease. Our results suggest that idelalisib is a promising treatment option for patients with TCF3-PBX1 BCP-ALL, whereas other drugs could be useful depending on the genetic context of individual patients.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Purinas / Proteínas de Fusión Oncogénica / Quinazolinonas / Leucemia-Linfoma Linfoblástico de Células Precursoras Tipo de estudio: Diagnostic_studies Límite: Adult / Humans / Male Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2017 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Purinas / Proteínas de Fusión Oncogénica / Quinazolinonas / Leucemia-Linfoma Linfoblástico de Células Precursoras Tipo de estudio: Diagnostic_studies Límite: Adult / Humans / Male Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2017 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Reino Unido