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FBXW7 mutations in acute myeloid leukemia

The F-Box and WD40 domain-containing protein 7 gene (FBXW7) is a tumor suppressor gene that encodes a protein that is part of the E3 ubiquitin ligase complex and which controls the turnover of various proteins including NOTCH1, MYC and Cyclin E. FBXW7 mutations have been implicated in various human cancers with several conserved mutational hotspots [1]. Within the hematologic realm, FBXW7 mutations are well described in T-lymphoblastic leukemia (TALL); the majority of reported mutations are missense and nonsense substitutions, with the two most commonly mutated sites affecting arginine at residues 465 and 505 [2,3]. However, FBXW7 mutations are rarely reported in acute myeloid leukemia (AML), with a large series showing only 9 out of 1540 patients (<1%) with FBXW7 mutations [4]. In this study, we report FBXW7 mutations in two cases of AML and detail their associated features. Seven hundred and one consecutive cases of AML from February 2013 to March 2017 were analyzed for FBXW7 mutations (exons 4–11, transcript ID NM_33632.3) by next-generation sequencing (NGS) using a gene panel consisting of a custom amplicon library that targets up to 68 genes. The libraries were sequenced on the Illumina MiSeq (Illumina Inc, San Diego, CA) platform via multiplexed, paired end reads. The threshold designated for laboratory quality control is a minimum 250x read depth at any given position, with 2000x mean coverage across the entire panel and incorrect base call probability of 1 in 1000 at greater than 95% of reads. FBXW7 mutations were identified in two of 701 AML cases (Table 1). Both are missense mutations known to be associated with loss of function (c.1394G>A p.R465H and c.1513C> T p.R505C) and are the most commonly mutated variants described in T-ALL. One case was a t(8;21) RUNX1/RUNX1T1 AML with an exclusive extramedullary presentation. The other was categorized as an AML, not otherwise specified. Although this case lacked a t(8;21) by both metaphase analysis and FISH, it was morphologically an AML with differentiation (equivalent to FAB M2) and harbored a del(9q), both of which are associated with AML with t(8;21). Both cases showed normal or near normal hemoglobin levels and platelet counts. Neither case expressed Tcell antigens with the presence of CD4 and CD7 not considered to be lineage specific. FBXW7 mutations are well described in T-ALL while only rarely reported in AML [5,6]. In fact, the 2013 TCGA series on AML [7] did not report any FBXW7 mutations, and a subsequent large series showed FBXW7 mutations to be infrequent and were observed in only 0.6% of patients [4]. We present two patients with AML that were found to have pathogenic FBXW7 mutations involving the two mutational sites commonly reported in T-ALL. It is possible that FBXW7 mutations may play a role in certain subtypes of AML. These may represent a novel disease associated pathway in myeloid neoplasia.