title: HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia.
abstract: Inhibitors of B-cell lymphoma-2 (BCL-2) such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, and then comprehensively assessed whether the responses correlated to specific mutations or gene expression signatures. Compared with samples from healthy donor controls (nonsensitive) and chronic lymphocytic leukemia (CLL) patients (highly sensitive), AML samples exhibited variable responses to BCL-2 inhibition. Strongest CLL-like responses were observed in 15% of the AML patient samples, whereas 32% were resistant, and the remaining exhibited intermediate responses to venetoclax. BCL-2 inhibitor sensitivity was associated with genetic aberrations in chromatin modifiers, WT1 and IDH1/IDH2. A striking selective overexpression of specific HOXA and HOXB gene transcripts were detected in highly BCL-2 inhibitor sensitive samples. Ex vivo responses to venetoclax showed significant inverse correlation to β2-microglobulin expression and to a lesser degree to BCL-XL and BAX expression. As new therapy options for AML are urgently needed, the specific HOX gene expression pattern can potentially be used as a biomarker to identify venetoclax-sensitive AML patients for clinical trials.
authors: Department of Hematology, Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors: M
authors: M
authors: Kontro
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: A
authors: A
authors: Kumar
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: M M
authors: MM
authors: Majumder
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: S
authors: 0000-0001-5056-4750
authors: S
authors: Eldfors
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: A
authors: A
authors: Parsons
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: T
authors: T
authors: Pemovska
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: J
authors: J
authors: Saarela
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: B
authors: B
authors: Yadav
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: D
authors: D
authors: Malani
authors: Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors: Y
authors: Y
authors: Fløisand
authors: Department of Hematology, Uppsala University Hospital, Uppsala, Sweden.
authors: M
authors: M
authors: Höglund
authors: Department of Clinical Hematology, Turku University Central Hospital, University of Turku, Turku, Finland.
authors: K
authors: K
authors: Remes
authors: Department of Clinical Science, Hematology Section, University of Bergen, Bergen, Norway.|Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway.
authors: B T
authors: BT
authors: Gjertsen
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: O
authors: 0000-0002-3231-0332
authors: O
authors: Kallioniemi
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: K
authors: K
authors: Wennerberg
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: C A
authors: CA
authors: Heckman
authors: Department of Hematology, Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors: K
authors: K
authors: Porkka
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001706:Biopsy; D001853:Bone Marrow / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059472:Exome; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D005801:Genes, Homeobox; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D005810:Multigene Family; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology; D025721:WT1 Proteins / Q000235:genetics; D001613:beta 2-Microglobulin / Q000235:genetics
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D025721:WT1 Proteins; D001613:beta 2-Microglobulin; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C579720:venetoclax; C528561:navitoclax