PuSH - Publication Server of Helmholtz Zentrum München: Exome sequencing identifies recurring <em>FLT3 </em>N676K mutations in core-binding factor leukemia.

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Opatz, S.* ; Polzer, H. ; Herold, T. ; Konstandin, N.P.* ; Ksienzyk, B.* ; Zellmeier, E.* ; Vosberg, S. ; Graf, A.* ; Krebs, S.* ; Blum, H.* ; Hopfner, K.P.* ; Kakadia, P.M.* ; Schneider, S.* ; Dufour, A.* ; Braess, J.* ; Sauerland, M.C.* ; Berdel, W.E.* ; Büchner, T.* ; Woermann, B.J.* ; Hiddemann, W. ; Spiekermann, K. ; Bohlander, S.K. ; Greif, P.A.

Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia.

Blood 122, 1761-1769 (2013)

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The t(8;21) and inv(16)/t(16;16) rearrangements affecting the core-binding factors, RUNX1 and CBFB, respectively, are found in 15-20% of adult de novo AML cases and are associated with a favourable prognosis. Since the expression of the fusion genes CBFB/MYH11 or RUNX1/RUNX1T1 alone is not sufficient to cause leukemia, we performed exome sequencing of an AML sample with an inv(16) to identify mutations, which may collaborate with the CBFB/MYH11 fusion during leukemogenesis. We discovered an N676K mutation in the ATP-binding domain (TKD1) of the fms-related tyrosine kinase 3 (FLT3) gene. In a cohort of 84 de novo AML patients with a CBFB/MYH11 rearrangement and in 36 patients with a RUNX1/RUNX1T1 rearrangement, the FLT3 N676K mutation was identified in 5 and 1 patients, respectively (5/84, 6%; 1/36, 3%). The FLT3-N676K mutant alone leads to factor-independent growth in Ba/F3 cells and, together with a concurrent FLT3-ITD, confers resistance to the FLT3 PTK inhibitors PKC412 and AC220. Gene expression analysis of AML patients with CBFB/MYH11 rearrangement and FLT3 N676K mutation showed a trend towards a specific expression profile. Ours is the first report of recurring FLT3 N676 mutations in CBF leukemias and suggests a defined subgroup of CBF leukemias. Registered at www.clinicaltrials.gov: AMLCG-1999 trial (NCT00266136).

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