Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice.
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and, in most cases, is of pro- or pre-B cell origin (B-ALL). The receptor tyrosine kinase KIT is expressed by hematopoietic stem and precursor cells. Gain-of-function mutations of KIT cause systemic mastocytosis, which is characterized by abnormal accumulations of mast cells. We previously reported a mouse model of mastocytosis based on conditional expression of a constitutively active Kit protein. Half of these animals developed leukemic disease of B-lineage origin. Herein, we report that this condition bears striking similarities to human B-ALL. The immuno-phenotype of the leukemic cells was compatible with a pro-B-cell origin, as was the finding of immunoglobulin heavy-chain gene rearrangements in all cases, whereas light-chain loci were mostly not rearranged. Leukemogenesis was independent of pre-B-cell receptor expression. Primary leukemic cells and permanent cell lines derived from these were serially transplantable and rapidly killed the recipients. In a few animals, the leukemia was of T-cell origin with abnormal CD4/8 double-positive T-cell precursors dominating in the circulation. In summary, we report a novel ALL mouse model that may prove useful for in vivo drug testing and identification of novel oncogenic mutations and principles.
Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.
Robin R
RR
Weidemann
Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.
Rayk
R
Behrendt
Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.
Kristina B
KB
Schoedel
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Werner
W
Müller
Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.
Axel
A
Roers
Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany. Electronic address: alexander.gerbaulet@tu-dresden.de.
Alexander
A
Gerbaulet
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D015322:Gene Rearrangement, B-Lymphocyte; D056426:Genetic Loci; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D016130:Immunophenotyping; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction
D015415:Biomarkers; D007143:Immunoglobulin Heavy Chains; D011947:Receptors, Antigen, B-Cell; D019009:Proto-Oncogene Proteins c-kit