title: Distinct classes of c-Kit-activating mutations differ in their ability to promote RUNX1-ETO-associated acute myeloid leukemia.
abstract: The t(8;21) RUNX1-ETO translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML). In RUNX1-ETO(+) patient samples, differing classes of activating c-KIT receptor tyrosine kinase mutations have been observed. The most common (12%-48%) involves mutations, such as D816V, which occur in the tyrosine kinase domain, whereas another involves mutations within exon 8 in a region mediating receptor dimerization (2%-13% of cases). To test whether distinct subtypes of activating c-KIT mutations differ in their leukemogenic potential in association with RUNX1-ETO, we used a retroviral transduction/transplantation model to coexpress RUNX1-ETO with either c-Kit(D814V) or c-Kit(T417IΔ418-419) in murine hematopoietic stem/progenitor cells used to reconstitute lethally irradiated mice. Analysis of reconstituted animals showed that RUNX1-ETO;c-Kit(D814V) coexpression resulted in 3 nonoverlapping phenotypes. In 45% of animals, a transplantable AML of relatively short latency and frequent granulocytic sarcoma was noted. Other mice exhibited a rapidly fatal myeloproliferative phenotype (35%) or a lethal, short-latency pre-B-cell leukemia (20%). In contrast, RUNX1-ETO;c-Kit(T417IΔ418-419) coexpression promoted exclusively AML in a fraction (51%) of reconstituted mice. These observations indicate that c-Kit(D814V) promotes a more varied and aggressive leukemic phenotype than c-Kit(T417IΔ418-419), which may be the result of differing potencies of the activating c-Kit alleles.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, AL 35294, USA.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Nick
authors.forename: Hyung-Gyoon
authors.initials: HG
authors.lastname: Kim
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Chang
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Harris
authors.forename: Vishnu
authors.initials: V
authors.lastname: Reddy
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klug
mesh_terms: D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D019009:Proto-Oncogene Proteins c-kit