Characterization of p190-Bcr-Abl chronic myeloid leukemia reveals specific signaling pathways and therapeutic targets
| Autor: | Matti Kankainen, Komal Kumar Javarappa, Soili Kytölä, Helena Hohtari, Satu Mustjoki, Swapnil Potdar, Shady Adnan-Awad, Kimmo Porkka, Caroline A. Heckman, Isabella Maria Mayer, Daehong Kim, Tania Brandstoetter, Veronika Sexl, Eszter Doma |
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| Přispěvatelé: | TRIMM - Translational Immunology Research Program, Department of Clinical Chemistry and Hematology, Hematologian yksikkö, HUS Comprehensive Cancer Center, Institute for Molecular Medicine Finland, Research Programs Unit, Helsinki University Hospital Area, HUSLAB, Clinicum, Department of Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Proteomics Cancer Research Transcription Genetic Fusion Proteins bcr-abl medicine.disease_cause Mice 0302 clinical medicine Interferon hemic and lymphatic diseases Cancer genomics Aged 80 and over 0303 health sciences Myeloid leukemia Hematology Middle Aged Precursor Cell Lymphoblastic Leukemia-Lymphoma Up-Regulation 3. Good health Leukemia Oncology 030220 oncology & carcinogenesis Female Signal Transduction Proto-oncogene tyrosine-protein kinase Src medicine.drug Cell signaling 3122 Cancers Hyperphosphorylation Biology Article 03 medical and health sciences Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive medicine Animals Humans Glucocorticoids neoplasms Oncogenesis Chronic myeloid leukaemia Aged 030304 developmental biology Gene Expression Profiling Imatinib Oncogenes Translational research medicine.disease Cancer research Carcinogenesis |
| Zdroj: | Leukemia |
| Popis: | The oncogenic protein Bcr-Abl has two major isoforms, p190Bcr-Abl and p210Bcr-Abl. While p210Bcr-Abl is the hallmark of chronic myeloid leukemia (CML), p190Bcr-Abl occurs in the majority of Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) patients. In CML, p190Bcr-Abl occurs in a minority of patients associating with distinct hematological features and inferior outcomes, yet the pathogenic role of p190Bcr-Abl and potential targeting therapies are largely uncharacterized. We employed next generation sequencing, phospho-proteomic profiling, and drug sensitivity testing to characterize p190Bcr-Abl in CML and hematopoietic progenitor cell line models (Ba/f3 and HPC-LSK). p190Bcr-Abl CML patients demonstrated poor response to imatinib and frequent mutations in epigenetic modifiers genes. In contrast with p210Bcr-Abl, p190Bcr-Abl exhibited specific transcriptional upregulation of interferon, interleukin-1 receptor, and P53 signaling pathways, associated with hyperphosphorylation of relevant signaling molecules including JAK1/STAT1 and PAK1 in addition to Src hyperphosphorylation. Comparable to p190Bcr-Abl CML patients, p190Bcr-Abl cell lines demonstrated similar transcriptional and phospho-signaling signatures. With the drug sensitivity screening we identified targeted drugs with specific activity in p190Bcr-Abl cell lines including IAP-, PAK1-, and Src inhibitors and glucocorticoids. Our results provide novel insights into the mechanisms underlying the distinct features of p190Bcr-Abl CML and promising therapeutic targets for this high-risk patient group. |
| Databáze: | OpenAIRE |
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