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.
journal_name
Bloodjournal_title
Bloodauthors
Nick HJ,Kim HG,Chang CW,Harris KW,Reddy V,Klug CAdoi
10.1182/blood-2011-02-338228subject
Has Abstractpub_date
2012-02-09 00:00:00pages
1522-31issue
6eissn
0006-4971issn
1528-0020pii
blood-2011-02-338228journal_volume
119pub_type
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