Recurrent ETNK1 mutations in atypical chronic myeloid leukemia

Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencin...

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Bibliographic Details
Published in:Blood 2015-01, Vol.125 (3), p.499-503
Main Authors: Gambacorti-Passerini, Carlo B., Donadoni, Carla, Parmiani, Andrea, Pirola, Alessandra, Redaelli, Sara, Signore, Giovanni, Piazza, Vincenzo, Malcovati, Luca, Fontana, Diletta, Spinelli, Roberta, Magistroni, Vera, Gaipa, Giuseppe, Peronaci, Marco, Morotti, Alessandro, Panuzzo, Cristina, Saglio, Giuseppe, Usala, Emilio, Kim, Dong-Wook, Rea, Delphine, Zervakis, Konstantinos, Viniou, Nora, Symeonidis, Argiris, Becker, Heiko, Boultwood, Jacqueline, Campiotti, Leonardo, Carrabba, Matteo, Elli, Elena, Bignell, Graham R., Papaemmanuil, Elli, Campbell, Peter J., Cazzola, Mario, Piazza, Rocco
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Case-Control Studies
Follow-Up Studies
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics
Leukemia, Myelomonocytic, Chronic - genetics
Molecular Sequence Data
Mutation - genetics
Phosphotransferases (Alcohol Group Acceptor) - genetics
Prognosis
Sequence Homology, Amino Acid
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Summary:Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identified somatic missense mutations in the ETNK1 gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of ETNK1 variants in 6 (8.8%) of 68 aCML and 2 (2.6%) of 77 chronic myelomonocytic leukemia samples. These mutations clustered in a small region of the kinase domain, encoding for H243Y and N244S (1/8 H243Y; 7/8 N244S). They were all heterozygous and present in the dominant clone. The intracellular phosphoethanolamine/phosphocholine ratio was, on average, 5.2-fold lower in ETNK1-mutated samples (P < .05). Similar results were obtained using myeloid TF1 cells transduced with ETNK1 wild type, ETNK1-N244S, and ETNK1-H243Y, where the intracellular phosphoethanolamine/phosphocholine ratio was significantly lower in ETNK1-N244S (0.76 ± 0.07) and ETNK1-H243Y (0.37 ± 0.02) than in ETNK1-WT (1.37 ± 0.32; P = .01 and P = .0008, respectively), suggesting that ETNK1 mutations may inhibit the catalytic activity of the enzyme. In summary, our study shows for the first time the evidence of recurrent somatic ETNK1 mutations in the context of myeloproliferative/myelodysplastic disorders. •Whole-exome sequencing reveals the presence of recurrent somatic mutations of ETNK1 in patients with atypical chronic myeloid leukemia.•ETNK1 mutations impair the catalytic activity of the enzyme, causing a decrease in the intracellular levels of phosphoethanolamine.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2014-06-579466