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:

Rapid conversion of chronic myeloid leukemia to chronic myelomonocytic leukemia in a patient on imatinib therapy

Leukemia volume 30, pages 2275–2279 (2016)Cite this article

Subjects

BCR-ABL1, the product of the Philadelphia chromosome (Ph), is sufficient for inducing the chronic phase of chronic myeloid leukemia (CML).1 Tyrosine kinase inhibitors (TKIs) suppress the Ph+ cell clone, restoring polyclonal hematopoiesis.2 However, clonal cytogenetic abnormalities in Ph− cells become detectable in some patients achieving a cytogenetic response to TKIs, and slow evolution to myelodysplasia or acute myeloid leukemia (AML) has been observed.2, 3 In rare cases, identical abnormalities were demonstrated both in Ph+ and Ph− cells, but most cases are consistent with independently acquired abnormalities, although an undetected common ancestral event cannot be excluded (reviewed in Loriaux and Deininger4). The clinical conundrum of coexisting leukemic disorders is that TKI suppression of CML may unmask a different, more aggressive disease. Here, we report a patient who after starting imatinib rapidly converted from CML to fatal chronic myelomonocytic leukemia (CMML), demonstrating that this is not a theoretical consideration. Whole-exome sequencing (WES) and genotyping of individual colonies revealed the clonal architecture during disease evolution and implicated TET2 and ASXL1 variants as early or germline events.

We performed WES (average read depth: 61 ×) on blood CD14+ cells from day 92, with CD3+ cells from the diagnostic sample as constitutional control. We identified four somatic single-nucleotide variants (SNVs; EZH2I669M, KRASG12R, MSLNP462H and NTRK3V443I), all of which were confirmed by Sanger sequencing (Supplementary Table 2). Sequenom MassARRAY (Agena Bioscience, San Diego, CA, USA) identified the same mutations in the day 67, 78, 92 and 124 samples, but not the diagnostic sample (Supplementary Table 3). In addition, we identified one nonsense variant in ASXL1 (c.24422delC→p.P808fs*10) and two nonsense variants in TET2 (TET2 c.1219delT→p.S407fs*20; c.4932delA→p.Y1645fs*50). Across all samples, including CD3+ and diagnostic CD14+ cells, ASXL1 c.24422delC and TET2 c.4932delA were detected at ~50%, whereas TET2 c.1219delT was detected at ~30% (Supplementary Table 3). ASXL1 c.24422delC and TET2 c.1219delT are listed in catalogue of somatic mutations in cancer and have been confirmed as somatic, whereas our findings are consistent with germline mutations or acquisition by a multipotent hematopoietic stem cell. Although TET2 c4932delA has not been reported in the catalogue of somatic mutations in cancer (COSMIC), a very similar variant (COSM4170135, c.4928delC, p.P1644fs*51) has. WES of the diagnostic sample at an average depth of 319 × failed to identify additional mutations specific to the CML clone, but confirmed the presence of low-level EZH2I669M, KRASG12R, MSLNP462H and NTRK3V443I.

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

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
Figure 2

References

  1. Deininger MW, Goldman JM, Melo JV . The molecular biology of chronic myeloid leukemia. Blood 2000; 96: 3343–3356.

    CAS  PubMed  Google Scholar 

  2. Bumm T, Muller C, Al-Ali HK, Krohn K, Shepherd P, Schmidt E et al. Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003; 101: 1941–1949.

    Article  CAS  PubMed  Google Scholar 

  3. Schmidt M, Rinke J, Schafer V, Schnittger S, Kohlmann A, Obstfelder E et al. Molecular-defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status. Leukemia 2014; 28: 2292–2299.

    Article  CAS  PubMed  Google Scholar 

  4. Loriaux M, Deininger M . Clonal cytogenetic abnormalities in Philadelphia chromosome negative cells in chronic myeloid leukemia patients treated with imatinib. Leuk Lymphoma 2004; 45: 2197–2203.

    Article  CAS  PubMed  Google Scholar 

  5. Diamond J, Goldman JM, Melo JV . BCR-ABL, ABL-BCR, BCR, and ABL genes are all expressed in individual granulocyte-macrophage colony-forming unit colonies derived from blood of patients with chronic myeloid leukemia. Blood 1995; 85: 2171–2175.

    CAS  PubMed  Google Scholar 

  6. Padron E, Abdel-Wahab O . Importance of genetics in the clinical management of chronic myelomonocytic leukemia. J Clin Oncol 2013; 31: 2374–2376.

    Article  CAS  PubMed  Google Scholar 

  7. Klco JM, Spencer DH, Miller CA, Griffith M, Lamprecht TL, O'Laughlin M et al. Functional heterogeneity of genetically defined subclones in acute myeloid leukemia. Cancer Cell 2014; 25: 379–392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Itzykson R, Kosmider O, Renneville A, Morabito M, Preudhomme C, Berthon C et al. Clonal architecture of chronic myelomonocytic leukemias. Blood 2013; 121: 2186–2198.

    Article  CAS  PubMed  Google Scholar 

  9. Mason CC, Khorashad JS, Tantravahi SK, Kelley TW, Zabriskie MS, Yan D et al. Age-related mutations and chronic myelomonocytic leukemia. Leukemia 2016; 30: 906–913.

    Article  CAS  PubMed  Google Scholar 

  10. Grossmann V, Kohlmann A, Eder C, Haferlach C, Kern W, Cross NC et al. Molecular profiling of chronic myelomonocytic leukemia reveals diverse mutations in >80% of patients with TET2 and EZH2 being of high prognostic relevance. Leukemia 2011; 25: 877–879.

    Article  CAS  PubMed  Google Scholar 

  11. Chang K, Pastan I . Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci USA 1996; 93: 136–140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Onda M, Nagata S, Ho M, Bera TK, Hassan R, Alexander RH et al. Megakaryocyte potentiation factor cleaved from mesothelin precursor is a useful tumor marker in the serum of patients with mesothelioma. Clin Cancer Res 2006; 12 (14 Pt 1): 4225–4231.

    Article  CAS  PubMed  Google Scholar 

  13. Dulak AM, Stojanov P, Peng S, Lawrence MS, Fox C, Stewart C et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet 2013; 45: 478–486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lannon CL, Sorensen PH . ETV6-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages. Semin Cancer Biol 2005; 15: 215–223.

    Article  CAS  PubMed  Google Scholar 

  15. Kim MS, Kim GM, Choi YJ, Kim HJ, Kim YJ, Jin W . TrkC promotes survival and growth of leukemia cells through Akt-mTOR-dependent up-regulation of PLK-1 and Twist-1. Mol Cells 2013; 36: 177–184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Derek Warner, director of Sequence and Genomics Core Facilities in the University of Utah and Jonathan Schumacher (ARUP) for their assistance with the pyrosequencing experiments. This work was supported by a Leukemia & Lymphoma Society (LLS) Translational Research Program Award (6086-12) (MWD) and an LLS Specialized Center of Research Program Award (GCNCR0314A-UTAH) (MWD). This work was also supported by the National Institutes of Health (NIH) National Cancer Institute (grants P01CA049639 (MWD), R01CA178397 (MWD and TO) and 5P30CA042014-24 (Huntsman Cancer Institute)), by the V Foundation for Cancer Research (MWD and TO) and by U01HG006513 (GTM). JSK was a Special Fellow of the LLS and was supported by a Translational Research Training in Hematology Award from the American Society of Hematology (ASH). AME was supported by the NIH National Cancer Institute (T32 CA093247) and a Career Development Award from LLS (5090-12), and is currently funded through a Scholar Award from ASH. AME also acknowledges support from the NIH Loan Repayment Program.

Author information

Authors and Affiliations

  1. Huntsman Cancer Institute, Deininger/O'Hare Research Laboratory, University of Utah, Salt Lake City, UT, USA

    J S Khorashad, S K Tantravahi, D Yan, A M Eiring, T Hein, A D Pomicter, T O'Hare & M W Deininger

  2. Department of Cellular Pathology, Centre for Haematology, Hammersmith Hospital, Imperial College London, London, UK

    J S Khorashad & A G Reid

  3. Department of Pediatrics, University of Utah, Salt Lake City, UT, USA

    C C Mason

  4. Department of Human Genetics, University of Utah, Salt Lake City, UT, USA

    Y Qiao & G T Marth

  5. Department of Pathology, Molecular Diagnostics Laboratory, Biorepository and Molecular Pathology Core at Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    K Gligorich

  6. Department of Pathology, University of Utah, Salt Lake City, UT, USA

    T W Kelley

  7. Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA

    T O'Hare & M W Deininger

Authors
  1. J S Khorashad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S K Tantravahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C C Mason
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A M Eiring
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Gligorich
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Hein
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A D Pomicter
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A G Reid
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. T W Kelley
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. G T Marth
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. T O'Hare
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M W Deininger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M W Deininger.

Ethics declarations

Competing interests

MWD is on the advisory board and is a consultant for Ariad, Incyte, Novartis and Pfizer, and serves on the advisory board for CTI BioPharma Corp. His laboratory receives research funding from Bristol-Myers Squibb, Celgene, Gilead and Novartis. The remaining authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khorashad, J., Tantravahi, S., Yan, D. et al. Rapid conversion of chronic myeloid leukemia to chronic myelomonocytic leukemia in a patient on imatinib therapy. Leukemia 30, 2275–2279 (2016). https://doi.org/10.1038/leu.2016.218

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2016.218

This article is cited by

Search

Advanced search

Quick links