Abstract:
:The t(8;21) and inv(16)/t(16;16) rearrangements affecting the core-binding factors RUNX1 and CBFB, respectively, are found in 15% to 20% of adult de novo acute myeloid leukemia (AML) cases and are associated with a favorable 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 adenosine triphosphate (ATP)-binding domain (tyrosine kinase domain 1 [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 [6%] of 84; 1 [3%] of 36). The FLT3-N676K mutant alone leads to factor-independent growth in Ba/F3 cells and, together with a concurrent FLT3-ITD (internal tandem duplication), confers resistance to the FLT3 protein tyrosine kinase inhibitors (PTKIs) PKC412 and AC220. Gene expression analysis of AML patients with CBFB/MYH11 rearrangement and FLT3 N676K mutation showed a trend toward a specific expression profile. Ours is the first report of recurring FLT3 N676 mutations in core-binding factor (CBF) leukemias and suggests a defined subgroup of CBF leukemias.
journal_name
Bloodjournal_title
Bloodauthors
Opatz S,Polzer H,Herold T,Konstandin NP,Ksienzyk B,Zellmeier E,Vosberg S,Graf A,Krebs S,Blum H,Hopfner KP,Kakadia PM,Schneider S,Dufour A,Braess J,Sauerland MC,Berdel WE,Büchner T,Woermann BJ,Hiddemann W,Spiekermadoi
10.1182/blood-2013-01-476473subject
Has Abstractpub_date
2013-09-05 00:00:00pages
1761-9issue
10eissn
0006-4971issn
1528-0020pii
blood-2013-01-476473journal_volume
122pub_type
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