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Blood, 15 August 2007, Vol. 110, No. 4, pp. 1308-1316.
Prepublished online as a Blood First Edition Paper on May 7, 2007; DOI 10.1182/blood-2007-02-072595.
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Submitted February 5, 2007
Accepted May 4, 2007
Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3-expression in acute myeloid leukemia
Frank Dicker*, Claudia Haferlach, Wolfgang Kern, Torsten Haferlach, and Susanne Schnittger
MLL, Munich Leukemia Laboratory, Munich, Germany
* Corresponding author; email: frank.dicker{at}mll-online.com.
AML1/RUNX1 is implicated in leukemogenesis on the basis of the AML1-ETO fusion transcript as well as somatic mutations in its DNA-binding domain. Somatic mutations in RUNX1 are preferentially detected in AML M0, myeloid malignancies with acquired trisomy 21 and certain MDS cases. By correlating the presence of RUNX1-mutations with cytogenetic and molecular aberration in a large cohort of AML M0 (n=90) at diagnosis, we detected RUNX1-mutations in 46% of cases with all trisomy 13 cases (n=18) being affected. No mutations of NRAS or KIT were detected in the RUNX1-mutated group and FLT3-mutations were equally distributed between RUNX1-mutated and unmutated samples. Likewise, a high incidence of RUNX1-mutations (80%) was detected in cases with trisomy 13 from other FAB subgroups (n=20). As FLT3 is localized on chromosome 13, we hypothesized that RUNX1-mutations might cooperate with trisomy 13 in leukemogenesis by increasing FLT3-transcript levels. Quantitation of FLT3-transcript levels revealed a highly significant (p < 0.001) about five-fold increase in AML with RUNX1-mutations and trisomy 13 compared to samples without trisomy 13. The results of the present study indicate that in the absence of FLT3 mutations, FLT3-overexpression might be a mechanism for FLT3-activation, which cooperates with RUNX1-mutations in leukemogenesis.
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