Leukemic transformation driven by an ASXL1 mutation after a JAK2V617F-positive primary myelofibrosis: clonal evolution and hierarchy revealed by next-generation sequencing
© Ferrer-Marín et al.; licensee BioMed Central Ltd. 2013
Received: 1 September 2013
Accepted: 3 September 2013
Published: 8 September 2013
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.
KeywordsMyelofibrosis ASXL1 Gene mutations Acute myeloid leukemia Clonality Next-generation sequencing
Letters to the editor
It is known that patients with JAK2V617F + myeloproliferative neoplasms (MPNs) can progress to a JAK2V617F¯ acute myeloid leukemia (AML)[1–3]. These two phases of the disease may represent two different clones, however, the time-dependent clonal hierarchy is just beginning to be elucidated[4, 5].
ASXL1 is the second most frequently mutated gene after JAK2 (~34.5%) in myelofibrosis (MF). ASXL1 mutations are also found in solid neoplasms and all types of myeloid malignancies. They are associated with aggressive disease but their role in leukemic transformation remains controversial. ASXL1 mutations correlated with progression to blast-state in myelodysplastic syndromes and chronic myelomonocytic leukaemia[9, 10] while in MF, they are detectable in most patients at diagnosis, and they are present in chronic- and blast-phases with the same prevalence. These findings suggest that ASXL1 mutations play a crucial role in the pathogenesis of MF[6, 11] but they do not directly cause a leukemic phenotype[2, 6]. We here characterize the molecular changes associated to the leukemic transformation of a patient with primary-MF (PMF) using next-generation sequencing (NGS). By the time of the hematologic progression, the patient also developed a lung adenocarcinoma. The relationship between the clonal hierarchy and phenotype disease over time are discussed.
Since ASXL1 has been involved in epithelial malignancy tumorigenesis and cancer, we sequenced ASXL1 gene in the hepatic metastatic tissue of lung cancer, but ASXL1-R693X mutation was not detected (Figure 2C), suggesting that at least three malignant clones might be present.
Overall, in this patient, at early disease, the PMF phenotype was driven mainly by a JAK2V617F + -dominant clone carrying trisomy 8. During the evolution this clone declined, whereas the ASXL1-mutated minor clone expanded, promoting the progression to leukemia. The reasons for these gradual shifts are unknown. Although hydroxyurea may induce a decrease in JAK2V617F allele burden in JAK2V617F + -MPNs[13, 19], leukemic transformation in MF can occur without any prior therapy. Furthermore, ASXL1-R693X mutation, as other mutations affecting genes with epigenetic role, likely favor the occurrence of secondary genetic events and, in association with other cooperating mutations, promotes blast-crisis.
The molecular mechanisms undergoing the myeloid leukemogenesis promoted by ASXL1 have been recently reported, but in MF, the role of ASXL1 mutations in leukemic transformation is still unclear[2, 6, 22]. By using NGS, we report, for the first time, an association between expansion of an ASXL1-mutated clone and MF progression to AML suggesting that in MF, as in other myeloid malignancies, ASXL1 mutations play a role in leukemic transformation. Given the prevalence of ASXL1 mutations in patients with MF, determination of ASXL1 mutation status in these patients could help in the molecular disease monitoring.
Written informed consent was obtained from the next of kin of the patient for publication of this Case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
We thank Dr J Corral for his helpful discussions.
- 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.View ArticlePubMedGoogle Scholar
- 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.PubMed CentralView ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- Jager R, Kralovics R: Molecular basis and clonal evolution of myeloproliferative neoplasms. Haematologica. 2010, 95: 526-529. 10.3324/haematol.2009.019570.PubMed CentralView ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.PubMed CentralView ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.PubMed CentralView ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.PubMed CentralView ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.PubMed CentralView ArticlePubMedGoogle Scholar
- 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.PubMed CentralView ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.