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Dutta, S. ; Krause, A.* ; Vosberg, S. ; Herold, T. ; Ksienzyk, B.* ; Quintanilla-Martinez, L.* ; Tizazu, B. ; Chopra, M.* ; Graf, A.* ; Krebs, S.* ; Blum, H.* ; Greif, P.A. ; Vetter, A. ; Metzeler, K.H. ; Rothenberg-Thurley, M.* ; Schneider, M.R.* ; Dahlhoff, M.* ; Spiekermann, K. ; Zimber-Strobl, U. ; Wolf, E.* ; Bohlander, S.K.

The target cell of transformation is distinct from the leukemia stem cell in murine CALM/AF10 leukemia models.

Leukemia 30, 1166-1176 (2016)
Publ. Version/Full Text Postprint DOI PMC
Open Access Green
The CALM/AF10 fusion gene is found in various hematological malignancies including AML, T-cell ALL, and malignant lymphoma. We have previously identified the leukemia stem cell (LSC) in a CALM/AF10-driven murine bone marrow transplant acute myeloid leukemia model as B220-positive 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 fusions gene preceded by a loxP-flanked transcriptional stop cassette into the Rosa26 locus. Vav-Cre induced pan-hematopoietic 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 co-expression of the B cell marker B220, and had clonal B-cell receptor rearrangements. Using whole-exome sequencing, we identified an average of 2 to 3 additional mutations per leukemia, including activating mutations in known oncogenes like FLT3 and PTPN11. Our results show that the COL for CALM/AF10 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-positive leukemia.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Acute Myeloid-leukemia; Acute Lymphoblastic-leukemia; Calm-af10 Fusion Gene; Molecular Characterization; Myeloblastic-leukemia; Bethesda Proposals; Transgenic Mice; Up-regulation; T-all; Protein
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Journal Leukemia
Quellenangaben Volume: 30, Issue: 5, Pages: 1166-1176 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)
Research Unit Gene Vector (AGV)
German Center for Diabetes Reseach (DZD)