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Open Access 01-12-2013 | Letter to the Editor

Leukemic transformation driven by an ASXL1 mutation after a JAK2V617F-positive primary myelofibrosis: clonal evolution and hierarchy revealed by next-generation sequencing

Authors: Francisca Ferrer-Marín, Beatriz Bellosillo, Luz Martínez-Avilés, Gloria Soler, Pablo Carbonell, Ginés Luengo-Gil, Eva Caparrós, José M Torregrosa, Carlos Besses, Vicente Vicente

Published in: Journal of Hematology & Oncology | Issue 1/2013

Abstract

We have characterized the molecular changes underlying the transformation of a JAK2V617F⁺-myelofibrosis with trisomy 8, into a JAK2V617F-negative leukemia. Leukemic clone did not carry JAK2V617F mutation, but showed ASXL1 mutation (R693X). This mutation was identified in a low percentage at diagnosis by next-generation sequencing. Using this technology in serial specimens during the follow-up, we observed a progressive expansion of the ASXL1-mutated minor clone, whereas the JAK2V617F⁺-clone carrying trisomy 8 decreased. Hematologic progression occurred simultaneously with an ASXL1-R693X-negative lung-cancer. This is the first report showing a clear association between the expansion of an ASXL1-mutated clone and the leukemic transformation of myelofibrosis.

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Beer PA, Delhommeau F, LeCouedic JP, Dawson MA, Chen E, Bareford D, Kusec R, McMullin MF, Harrison CN, Vannucchi AM: Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood. 2010, 115: 2891-2900. 10.1182/blood-2009-08-236596.CrossRefPubMed

Abdel-Wahab O, Manshouri T, Patel J, Harris K, Yao J, Hedvat C, Heguy A, Bueso-Ramos C, Kantarjian H, Levine RL, Verstovsek S: Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. Cancer Res. 2010, 70: 447-452. 10.1158/0008-5472.CAN-09-3783.PubMedCentralCrossRefPubMed

Theocharides A, Boissinot M, Girodon F, Garand R, Teo SS, Lippert E, Talmant P, Tichelli A, Hermouet S, Skoda RC: Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood. 2007, 110: 375-379. 10.1182/blood-2006-12-062125.CrossRefPubMed

Jager R, Kralovics R: Molecular basis and clonal evolution of myeloproliferative neoplasms. Haematologica. 2010, 95: 526-529. 10.3324/haematol.2009.019570.PubMedCentralCrossRefPubMed

Vainchenker W, Delhommeau F, Constantinescu SN, Bernard OA: New mutations and pathogenesis of myeloproliferative neoplasms. Blood. 2011, 118: 1723-1735. 10.1182/blood-2011-02-292102.CrossRefPubMed

Stein BL, Williams DM, O’Keefe C, Rogers O, Ingersoll RG, Spivak JL, Verma A, Maciejewski JP, McDevitt MA, Moliterno AR: Disruption of the ASXL1 gene is frequent in primary, post-essential thrombocytosis and post-polycythemia vera myelofibrosis, but not essential thrombocytosis or polycythemia vera: analysis of molecular genetics and clinical phenotypes. Haematologica. 2011, 96: 1462-1469. 10.3324/haematol.2011.045591.PubMedCentralCrossRefPubMed

Abdel-Wahab O, Dey A: The ASXL-BAP1 axis: new factors in myelopoiesis, cancer and epigenetics. Leukemia. 2013, 27: 10-15. 10.1038/leu.2012.288.CrossRefPubMed

Gelsi-Boyer V, Brecqueville M, Devillier R, Murati A, Mozziconacci MJ, Birnbaum D: Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases. J Hematol Oncol. 2012, 5: 12-10.1186/1756-8722-5-12.PubMedCentralCrossRefPubMed

Thol F, Friesen I, Damm F, Yun H, Weissinger EM, Krauter J, Wagner K, Chaturvedi A, Sharma A, Wichmann M: Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes. J Clin Oncol. 2011, 29: 2499-2506. 10.1200/JCO.2010.33.4938.CrossRefPubMed

10.

Gelsi-Boyer V, Trouplin V, Roquain J, Adelaide J, Carbuccia N, Esterni B, Finetti P, Murati A, Arnoulet C, Zerazhi H: ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia. Br J Haematol. 2010, 151: 365-375. 10.1111/j.1365-2141.2010.08381.x.CrossRefPubMed

11.

Ricci C, Spinelli O, Salmoiraghi S, Finazzi G, Carobbio A, Rambaldi A: ASXL1 mutations in primary and secondary myelofibrosis. Br J Haematol. 2012, 156: 404-407. 10.1111/j.1365-2141.2011.08865.x.CrossRefPubMed

12.

Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, Vannucchi AM, Mesa RA, Demory JL, Barosi G: New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009, 113: 2895-2901. 10.1182/blood-2008-07-170449.CrossRefPubMed

13.

Besses C, Alvarez-Larran A, Martinez-Aviles L, Mojal S, Longaron R, Salar A, Florensa L, Serrano S, Bellosillo B: Modulation of JAK2 V617F allele burden dynamics by hydroxycarbamide in polycythaemia vera and essential thrombocythaemia patients. Br J Haematol. 2011, 152: 413-419. 10.1111/j.1365-2141.2010.08467.x.CrossRefPubMed

14.

Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005, 352: 1779-1790. 10.1056/NEJMoa051113.CrossRefPubMed

15.

Martinez-Aviles L, Besses C, Alvarez-Larran A, Torres E, Serrano S, Bellosillo B: TET2, ASXL1, IDH1, IDH2, and c-CBL genes in JAK2- and MPL-negative myeloproliferative neoplasms. Ann Hematol. 2012, 91: 533-541. 10.1007/s00277-011-1330-0.CrossRefPubMed

16.

Martinez-Aviles L, Alvarez-Larran A, Besses C, Navarro G, Torres E, Longaron R, Angona A, Pedro C, Florensa L, Serrano S, Bellosillo B: Clinical significance of clonality assessment in JAK2V617F-negative essential thrombocythemia. Ann Hematol. 2012, 91: 1555-1562. 10.1007/s00277-012-1502-6.CrossRefPubMed

17.

Pietra D, Brisci A, Rumi E, Boggi S, Elena C, Pietrelli A, Bordoni R, Ferrari M, Passamonti F, De Bellis G: Deep sequencing reveals double mutations in cis of MPL exon 10 in myeloproliferative neoplasms. Haematologica. 2011, 96: 607-611. 10.3324/haematol.2010.034793.PubMedCentralCrossRefPubMed

18.

Scotto L, Narayan G, Nandula SV, Arias-Pulido H, Subramaniyam S, Schneider A, Kaufmann AM, Wright JD, Pothuri B, Mansukhani M, Murty VV: Identification of copy number gain and overexpressed genes on chromosome arm 20q by an integrative genomic approach in cervical cancer: potential role in progression. Genes Chromosomes Cancer. 2008, 47: 755-765. 10.1002/gcc.20577.CrossRefPubMed

19.

Girodon F, Schaeffer C, Cleyrat C, Mounier M, Lafont I, Santos FD, Duval A, Maynadie M, Hermouet S: Frequent reduction or absence of detection of the JAK2-mutated clone in JAK2V617F-positive patients within the first years of hydroxyurea therapy. Haematologica. 2008, 93: 1723-1727. 10.3324/haematol.13081.CrossRefPubMed

20.

Bjorkholm M, Derolf AR, Hultcrantz M, Kristinsson SY, Ekstrand C, Goldin LR, Andreasson B, Birgegard G, Linder O, Malm C: Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms. J Clin Oncol. 2011, 29: 2410-2415. 10.1200/JCO.2011.34.7542.PubMedCentralCrossRefPubMed

21.

Abdel-Wahab O, Adli M, LaFave LM, Gao J, Hricik T, Shih AH, Pandey S, Patel JP, Chung YR, Koche R: ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012, 22: 180-193. 10.1016/j.ccr.2012.06.032.PubMedCentralCrossRefPubMed

22.

Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A, Finke C, Score J, Gangat N, Mannarelli C: Mutations and prognosis in primary myelofibrosis. Leukemia. 2013, 27: 1861-1869. 10.1038/leu.2013.119.CrossRefPubMed

Title: Leukemic transformation driven by an ASXL1 mutation after a JAK2V617F-positive primary myelofibrosis: clonal evolution and hierarchy revealed by next-generation sequencing
Authors: Francisca Ferrer-Marín
Beatriz Bellosillo
Luz Martínez-Avilés
Gloria Soler
Pablo Carbonell
Ginés Luengo-Gil
Eva Caparrós
José M Torregrosa
Carlos Besses
Vicente Vicente
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2013
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/1756-8722-6-68

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