Mohammad Taghi Yaghmaie - Universit ¨at M¨unchen, M¨unchen, Germany
P Greuf - Tehran University of Medical Sciences, hematology, oncology and stem cell transplantation research center, Tehran, Iran
B Jibstandin - Tehran University of Medical Sciences, hematology, oncology and stem cell transplantation research center, Tehran, Iran
K Alimoghaddam - Tehran University of Medical Sciences, hematology, oncology and stem cell transplantation research center, Tehran, Iran

The t(15;17) translocation which results in the PML/RARA fusion is the disease defining lesion in nearly all cases of acute promyelocytic leukemia (APL). Despite the importance of the PML/RARA fusion for the pathogenesis of APL it is most likely not sufficient to cause leukemia alone. For example, collaborating mutations affecting the FLT3 receptor tyrosine kinase are found in about 20−30% of APL patients. To screen systematically for additional mutations, we performed whole exome sequencing of 3 APL patients. Thereby, we generated at least 5 Gbp of exome sequence for each of the APL samples and for each of the corresponding remission samples. This allowed us to cover at least 80% of RefSeq coding exon positions with a minimum read depth of 10 and at least 75% of RefSeq coding exon positions with minimum read depth of 20. By comparing the APL exome sequence with the remission exome sequence, we screened for small APL-specific genetic variants. We were able to confirm 3 to 5 somatic mutations per patient by Sanger sequencing. These APL specific mutations affected not only known mutational targets in leukemia, such as WT1 and KRAS, but also genes with potential implications in leukomogenesis, such as LYN, encoding a kinase which acts downstream of FLT3, and a novel homeobox gene. Our findings demonstrate that exome sequencing is an efficient method to screen for leukemia specific point mutations and small indels that may collaborate with the PML/RARA fusion during the onset and progression of APL.

Acute promyelocytic leukemia, exom sequencing, somatic mutation