A Curious Novel Combination of () Gene Mutations Leading to Aberrant Cytoplasmic Dislocation of in Acute Myeloid Leukemia (AML).

mutations occurring in acute myeloid leukemia (AML) (about 50 so far identified) cluster almost exclusively in exon 12 and lead to common changes at the mutants C-terminus, i.e., loss of tryptophans 288 and 290 (or 290 alone) and creation of a new nuclear export signal (NES), at the bases of exportin-1(XPO1)-mediated aberrant cytoplasmic . Immunohistochemistry (IHC) detects cytoplasmic and is predictive of the molecular alteration. Besides IHC and molecular sequencing, Western blotting (WB) with anti- mutant specific antibodies is another approach to identify -mutated AML. Here, we show that among 382 AML cases with exon 12 mutations, one was not recognized by WB, and describe the discovery of a novel combination of two mutations involving exon 12. This appeared as a conventional mutation A with the known TCTG nucleotides insertion/duplication accompanied by a second event (i.e., an 8-nucleotide deletion occurring 15 nucleotides downstream of the TCTG insertion), resulting in a new C-terminal protein sequence. Strikingly, the sequence included a functional NES ensuring cytoplasmic relocation of the new mutant supporting the role of cytoplasmic as critical in AML leukemogenesis.