Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Mutation analysis of TET2, IDH1, IDH2 and ASXL1 in chronic myeloid leukemia

Leukemia volume 25, pages 1661–1664 (2011)Cite this article

Subjects

Acquired somatic mutations affecting TET oncogene family number 2 (TET2), isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and additional sex combs-like 1 (ASXL1) have been recently described in BCR–ABL-negative neoplasm, myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS), MDS/MPN and acute myeloid leukemias (AMLs), including transformations of MDS or MPN.1 TET2 mutations are diverse (frameshift, nonsense and missense mutations) and do not cluster in a particular region of the protein. In contrast, mutations affecting IDH1/2 and ASXL1 are found in restricted regions.2, 3 None of these gene alterations are disease-specific and their incidence ranges from rare to 40%.1 Another important observation from recent related studies is that these mutations can coexist with other pathogenetically relevant mutations including JAK2V617F, sometimes before or emerging in a subclone.4 Therefore, and especially in view of the occurrence of these mutations across varying molecular profiles, their contribution to disease initiation, clonal evolution or blastic transformation is not clear. Also, the possibility of independently emerging multiple abnormal clones rather than monoclonal myeloproliferation is raised. In chronic myeloid leukemia (CML), BCR–ABL fusion is known to be the driver mutation. However, leukemogenesis is a complex process, and genomic heterogeneity of the chronic phase (CP) of the disease has been reported.5 This intrinsic heterogeneity at the molecular level could support a causative link with the varying response to treatment and disease progression. Furthermore, we still do not know for sure whether the BCR–ABL fusion is really the initiating lesion. In order to describe TET2, IDH1, IDH2 and ASXL1 mutation prevalence, to investigate whether these defects could represent an important event in CML initiation, and to define the relationships between acquisition of these mutations and CML transformation and/or imatinib (IM) resistance, here we report on a mutation analysis done on paired samples from CML at diagnosis (untreated), time of IM response and, when available, complete cytogenetic response (CCR) in 91 CML patients treated with IM as first line—most of them from the French SPIRIT trial—and presenting five profiles of IM response at the time of analysis: (1) 25 had CCR and major molecular response (MMR) at 12 months of IM; (2) 11 were in CCR but showed a Ph negative (Ph−) clonal evolution 12–24 months after IM (median 12 months); (3) 20 were in partial cytogenetic response (4 minor and 16 major), 3 of them with additional cytogenetic abnormalities (−Y, +8, +8) 18 months after IM and referred as primary resistant (R1); (4) 20 were in acute transformation (14 myeloid, 6 lymphoid) 4–72 months after onset of IM (median 12 months); and (5) 15 referred as secondary IM-resistant (R2) had relapse in CP (4 molecular relapse, 6 loss of CCR and 5 hematologic relapse). Sokal scores were homogeneously distributed among the five groups except for group 2, which did not have higher scores. Except for group 1, BCR–ABL residual disease evaluated by RQ-PCR remained high (median value 0.09%, according to the International Scale (IS)).

Genomic DNA was extracted from bone marrow or peripheral blood mononuclear cells at diagnosis or at time of IM response using standard procedures. The search for mutation was performed by sequencing the entire TET2 coding gene (11 exons), the IDH1 and IDH2 exon 4 and the ASXL1 exon 12. For the TET2 p.P1617fs (C4851del) mutation, ASO-PCR detection was performed on DNA obtained from the healthy donor or unique patient number (UPN) 2 at the time of myeloid transformation or at diagnosis. For the common p.G646WfsX12 (c.1934dupG), five repeated and independent sequencing analyses confirmed the somatic status of this specific variation, as it was always found in patients' samples but was not found among the 50 healthy DNA samples from donors.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Tefferi A . Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 2010; 24: 1128–1138.

    Article  CAS  Google Scholar 

  2. Kosmider O, Gelsi-Boyer V, Slama L, Dreyfus F, Beyne-Rauzy O, Quesnel B et al. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 2010; 24: 1094–1096.

    Article  CAS  Google Scholar 

  3. Chou WC, Huang HH, Hou HA, Chen CY, Tang JL, Yao M et al. Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations. Blood 2010; 116: 4086–4094.

    Article  CAS  Google Scholar 

  4. Schaub FX, Looser R, Li S, Hao-Shen H, Lehmann T, Tichelli A et al. Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms. Blood 2010; 115: 2003–2007.

    Article  CAS  Google Scholar 

  5. Khorashad JS, De Melo VA, Fiegler H, Gerrard G, Marin D, Apperley JF et al. Multiple sub-microscopic genomic lesions are a universal feature of chronic myeloid leukaemia at diagnosis. Leukemia 2008; 22: 1806–1807.

    Article  CAS  Google Scholar 

  6. Pardanani A, Lasho TL, Finke CM, Mai M, McClure RF, Tefferi A . IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms. Leukemia 2010; 24: 1146–1151.

    Article  CAS  Google Scholar 

  7. Soverini S, Score J, Iacobucci I, Poerio A, Lonetti A, Gnani A et al. IDH2 somatic mutations in chronic myeloid leukemia patients in blast crisis. Leukemia 2011; 25: 178–181.

    Article  CAS  Google Scholar 

  8. Boultwood J, Perry J, Zaman R, Fernandez-Santamaria C, Littlewood T, Kusec R et al. High-density single nucleotide polymorphism array analysis and ASXL1 gene mutation screening in chronic myeloid leukemia during disease progression. Leukemia 2010; 24: 1139–1145.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre, Lille, France

    C Roche-Lestienne & E Labis

  2. Laboratoire d'Hématologie, Centre de Biologie Pathologie, CHU Lille, Lille, France

    A Marceau, O Nibourel, N Helevaut, C Frimat & C Preudhomme

  3. Service des maladies du sang, Hôpital Huriez - CHRU, Lille, France

    V Coiteux

  4. CIC-P Inserm 802, Centre Hospitalier Jean Bernard, Poitiers, France

    J Guilhot & F Guilhot

  5. Service d'Hématologie, Hôpital de l'Archet, Nice, France

    L Legros

  6. Pavillon E Département d'Hématologie, Hôpital E. Herriot, Lyon, France

    F Nicolini

  7. Service d'Hématologie et d'Oncologie, Hôpital André Mignot, Le Chesnay, France

    P Rousselot

  8. Service des Maladies du sang, CHU Angers, Angers, France

    M Gardembas

  9. Laboratoire d'Hématologie et Service des Maladies du Sang, Université Victor Segalen, Bordeaux, France

    F-X Mahon

Authors
  1. C Roche-Lestienne
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Marceau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Labis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. O Nibourel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V Coiteux
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Guilhot
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Legros
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F Nicolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Rousselot
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Gardembas
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. N Helevaut
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. C Frimat
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. F-X Mahon
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. F Guilhot
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. C Preudhomme
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on the behalf of the Fi-LMC group

Corresponding author

Correspondence to C Preudhomme.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roche-Lestienne, C., Marceau, A., Labis, E. et al. Mutation analysis of TET2, IDH1, IDH2 and ASXL1 in chronic myeloid leukemia. Leukemia 25, 1661–1664 (2011). https://doi.org/10.1038/leu.2011.139

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.139

This article is cited by

Search

Advanced search

Quick links