The target cell of transformation is distinct from the leukemia stem cell in murine CALM/AF10 leukemia models
| Autor: | Maik Dahlhoff, Stefan Krebs, Helmut Blum, Eckhard Wolf, Maja Rothenberg-Thurley, K. Spiekermann, Belay Tizazu, U Zimber-Strobl, Sebastian Vosberg, Stefan K. Bohlander, Sayantanee Dutta, A T Vetter, Alexander Graf, Tobias Herold, Klaus H. Metzeler, Martin Chopra, Marlon R. Schneider, Bianka Ksienzyk, Alexandre Krause, Leticia Quintanilla-Martinez, Philipp A. Greif |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Cancer Research Myeloid Oncogene Proteins Fusion Biology 03 medical and health sciences Mice hemic and lymphatic diseases medicine Animals Exome Progenitor cell Acute leukemia B-Lymphocytes ABL Leukemia Experimental Myeloid leukemia Hematology Sequence Analysis DNA medicine.disease Leukemia Haematopoiesis 030104 developmental biology medicine.anatomical_structure Cell Transformation Neoplastic Oncology Mutation Cancer research Neoplastic Stem Cells Stem cell Genetic Engineering |
| Zdroj: | Leukemia. 30(5) |
| ISSN: | 1476-5551 |
| Popis: | The CALM/AF10 fusion gene is found in various hematological malignancies including acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia and malignant lymphoma. We have previously identified the leukemia stem cell (LSC) in a CALM/AF10-driven murine bone marrow transplant AML model as B220+ lymphoid cells with B-cell characteristics. To identify the target cell for leukemic transformation or 'cell of origin of leukemia' (COL) in non-disturbed steady-state hematopoiesis, we inserted the CALM/AF10 fusion gene preceded by a loxP-flanked transcriptional stop cassette into the Rosa26 locus. Vav-Cre-induced panhematopoietic expression of the CALM/AF10 fusion gene led to acute leukemia with a median latency of 12 months. Mice expressing CALM/AF10 in the B-lymphoid compartment using Mb1-Cre or CD19-Cre inducer lines did not develop leukemia. Leukemias had a predominantly myeloid phenotype but showed coexpression of the B-cell marker B220, and had clonal B-cell receptor rearrangements. Using whole-exome sequencing, we identified an average of two to three additional mutations per leukemia, including activating mutations in known oncogenes such as FLT3 and PTPN11. Our results show that the COL for CALM/AF10 leukemia is a stem or early progenitor cell and not a cell of B-cell lineage with a phenotype similar to that of the LSC in CALM/AF10+ leukemia. |
| Databáze: | OpenAIRE |
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