Recurrent ETNK1 mutations in atypical chronic myeloid leukemia

Carlo B. Gambacorti-Passerini, Carla Donadoni, Andrea Parmiani, Alessandra Pirola, Sara Redaelli, Giovanni Signore, Vincenzo Piazza, Luca Malcovati, Diletta Fontana, Roberta Spinelli, Vera Magistroni, Giuseppe Gaipa, Marco Peronaci, Alessandro Morotti, Cristina Panuzzo, Giuseppe Saglio, Emilio Usala, Dong Wook Kim, Delphine Rea, Konstantinos ZervakisNora Viniou, Argiris Symeonidis, Heiko Becker, Jacqueline Boultwood, Leonardo Campiotti, Matteo Carrabba, Elena Elli, Graham R. Bignell, Elli Papaemmanuil, Peter J. Campbell, Mario Cazzola, Rocco Piazza

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)499-503
Number of pages5
JournalBlood
Volume125
Issue number3
DOIs
Publication statusPublished - Jan 15 2015

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Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
Phosphorylcholine
Mutation
Catalyst activity
Phosphotransferases
Genes
Leukemia, Myelomonocytic, Chronic
Exome
Myeloproliferative Disorders
Myeloid Cells
Missense Mutation
Enzymes
Clone Cells
phosphorylethanolamine

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Gambacorti-Passerini, C. B., Donadoni, C., Parmiani, A., Pirola, A., Redaelli, S., Signore, G., ... Piazza, R. (2015). Recurrent ETNK1 mutations in atypical chronic myeloid leukemia. Blood, 125(3), 499-503. https://doi.org/10.1182/blood-2014-06-579466

Recurrent ETNK1 mutations in atypical chronic myeloid leukemia. / 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.

In: Blood, Vol. 125, No. 3, 15.01.2015, p. 499-503.

Research output: Contribution to journalArticle

Gambacorti-Passerini, CB, Donadoni, C, Parmiani, A, Pirola, A, Redaelli, S, Signore, G, Piazza, V, Malcovati, L, Fontana, D, Spinelli, R, Magistroni, V, Gaipa, G, Peronaci, M, Morotti, A, Panuzzo, C, Saglio, G, Usala, E, Kim, DW, Rea, D, Zervakis, K, Viniou, N, Symeonidis, A, Becker, H, Boultwood, J, Campiotti, L, Carrabba, M, Elli, E, Bignell, GR, Papaemmanuil, E, Campbell, PJ, Cazzola, M & Piazza, R 2015, 'Recurrent ETNK1 mutations in atypical chronic myeloid leukemia', Blood, vol. 125, no. 3, pp. 499-503. https://doi.org/10.1182/blood-2014-06-579466
Gambacorti-Passerini CB, Donadoni C, Parmiani A, Pirola A, Redaelli S, Signore G et al. Recurrent ETNK1 mutations in atypical chronic myeloid leukemia. Blood. 2015 Jan 15;125(3):499-503. https://doi.org/10.1182/blood-2014-06-579466
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. / Recurrent ETNK1 mutations in atypical chronic myeloid leukemia. In: Blood. 2015 ; Vol. 125, No. 3. pp. 499-503.
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abstract = "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.",
author = "Gambacorti-Passerini, {Carlo B.} and Carla Donadoni and Andrea Parmiani and Alessandra Pirola and Sara Redaelli and Giovanni Signore and Vincenzo Piazza and Luca Malcovati and Diletta Fontana and Roberta Spinelli and Vera Magistroni and Giuseppe Gaipa and Marco Peronaci and Alessandro Morotti and Cristina Panuzzo and Giuseppe Saglio and Emilio Usala and Kim, {Dong Wook} and Delphine Rea and Konstantinos Zervakis and Nora Viniou and Argiris Symeonidis and Heiko Becker and Jacqueline Boultwood and Leonardo Campiotti and Matteo Carrabba and Elena Elli and Bignell, {Graham R.} and Elli Papaemmanuil and Campbell, {Peter J.} and Mario Cazzola and Rocco Piazza",
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AU - Redaelli, Sara

AU - Signore, Giovanni

AU - Piazza, Vincenzo

AU - Malcovati, Luca

AU - Fontana, Diletta

AU - Spinelli, Roberta

AU - Magistroni, Vera

AU - Gaipa, Giuseppe

AU - Peronaci, Marco

AU - Morotti, Alessandro

AU - Panuzzo, Cristina

AU - Saglio, Giuseppe

AU - Usala, Emilio

AU - Kim, Dong Wook

AU - Rea, Delphine

AU - Zervakis, Konstantinos

AU - Viniou, Nora

AU - Symeonidis, Argiris

AU - Becker, Heiko

AU - Boultwood, Jacqueline

AU - Campiotti, Leonardo

AU - Carrabba, Matteo

AU - Elli, Elena

AU - Bignell, Graham R.

AU - Papaemmanuil, Elli

AU - Campbell, Peter J.

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AU - Piazza, Rocco

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N2 - 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.

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