title: Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: S
authors.identifier: 0000-0001-5056-4750
authors.initials: S
authors.lastname: Eldfors
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.|Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Kuusanmäki
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Kontro
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: M M
authors.initials: MM
authors.lastname: Majumder
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Parsons
authors.affiliation: MediSapiens Ltd., Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Edgren
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Pemovska
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: O
authors.identifier: 0000-0002-3231-0332
authors.initials: O
authors.lastname: Kallioniemi
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Wennerberg
authors.affiliation: Department of Medicine II, Goethe University, Frankfurt, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Gökbuget
authors.affiliation: Charité Universtätsmedizin Berlin, Med. Klinik für Hämatologie, Onkologie und Tumorimmunologie, Berlin, Germany.
authors.forename: T
authors.identifier: 0000-0003-4843-2876
authors.initials: T
authors.lastname: Burmeister
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Porkka
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: C A
authors.initials: CA
authors.lastname: Heckman
mesh_terms: D000328:Adult; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use; D052999:Quinazolinones / Q000494:pharmacology* / Q000627:therapeutic use; D012008:Recurrence
chemical_list: D015514:Oncogene Proteins, Fusion; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; C543638:TCF3-PBX1 fusion protein, human; D058543:Class Ia Phosphatidylinositol 3-Kinase; C552946:idelalisib