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.

  • Reply
  • Published:

Cell-cycle deregulation in progressive CML

Nature Reviews Cancer volume 8, page 563 (2008)Cite this article

Access through your institution
Buy or subscribe

There are alternative splice variants for CDKN2A and, in their correspondence on our Review (Savona, M. & Talpaz, M. Getting to the stem of chronic myeloid leukemia. Nature Rev. Cancer 8, 341–350), Williams and Sherr correctly note that one of these variants is translated through an alternate reading frame (hence, ARF), which acts by stabilizing p53 protein levels by inhibiting MDM2-mediated ubiquination and degradation1,2. We apologize for oversimplifying this molecular biology; indeed, ARF does not inhibit cyclin-dependent kinases (specifically, CDK4 and CDK6) as INK4A does, and we thank Williams and Sherr for clarifying this point. We failed to describe this important nuance in our efforts to express the known direct relationships between BCR–ABL and these tumour suppressors, their influence on G1 in the cell cycle, and their net pro-senescence effects. This was the planned design of the discussion on tumour suppressors in the latter half of our manuscript3.

Absence of the CDKN2A locus is a popular theme in liquid malignancies, and has been noted as a hallmark of aggressive disease in lymphocytic leukaemias for many years.4,5 At this point, it is still not clear whether the CDKN2A locus is deleted solely in lymphoid blast crisis, and not myeloid blast crisis chronic myeloid leukaemia (CML), as Williams and Sherr contend. There are early experimental data of loss of this locus also in myeloid malignancies6,7,8, and recent genomic analyses do not expressively indicate that this aberrancy is germane to lymphoid blast crisis, and exclusive of myeloid blast crisis or the rare entity Philadelphia chromosome (Ph)+ acute myeloid leukaemia (AML)9,10. That said, the authors have provided clear evidence that aberrancy of the CDKN2A locus is common and important in lymphoid leukaemias.

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

References

  1. Bixby, D., Kujawski, L., Wang, S. & Malek, S. N. The pre-clinical development of MDM2 inhibitors in chronic lymphocytic leukemia uncovers a central role for p53 status in sensitivity to Mdm2 inhibitor-mediated apoptosis. Cell Cycle 7, 971–979 (2008).

    Article  CAS  Google Scholar 

  2. Williams, R. T. & Sherr, C. J. BCR–ABL and CDKN2A: a dropped connection. Nature Rev. Cancer 8, 563 (2008).

    Article  CAS  Google Scholar 

  3. Savona, M. & Talpaz, M. Getting to the stem of chronic myeloid leukaemia. Nature Rev. Cancer 8, 341–350 (2008).

    Article  CAS  Google Scholar 

  4. Heerema, N. A. et al. Secondary cytogenetic aberrations in childhood Philadelphia chromosome positive acute lymphoblastic leukemia are nonrandom and may be associated with outcome. Leukemia 18, 693–702 (2004).

    Article  CAS  Google Scholar 

  5. Schoppmeyer, K., Norris, P. S. & Haas, M. Inhibition of T-cell acute lymphoblastic leukemia proliferation in vivo by re-expression of the p16INK4a tumor suppressor gene. Neoplasia 1, 128–137 (1999).

    Article  CAS  Google Scholar 

  6. Ahuja, H., Bar-Eli, M., Advani, S. H., Benchimol, S. & Cline, M. J. Alterations in the p53 gene and the clonal evolution of the blast crisis of chronic myelocytic leukemia. Proc. Natl Acad. Sci. USA 86, 6783–6787 (1989).

    Article  CAS  Google Scholar 

  7. Calabretta, B., Perrotti, D. The biology of CML blast crisis. Blood 103, 4010–4022 (2004).

    Article  CAS  Google Scholar 

  8. Feinstein, E. et al. p53 in chronic myelogenous leukemia in acute phase. Proc. Natl Acad. Sci. USA 88, 6293–6297 (1991).

    Article  CAS  Google Scholar 

  9. Williams RT, den Besten, W. & Sherr, C. J. Cytokine-dependent imatinib resistance in mouse BCR-ABL+, Arf-null lymphoblastic leukemia. Genes Dev. 21, 2283–2287 (2007).

    Article  CAS  Google Scholar 

  10. Williams, R. T., Roussel, M. F. & Sherr, C. J. Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr–Abl-induced acute lymphoblastic leukemia. Proc. Natl Acad. Sci. USA 103, 6688–6693 (2006).

    Article  CAS  Google Scholar 

  11. Mirebeau, D. et al. The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood. Results of the EORTC studies 58881 and 58951. Haematologica 91, 881–885 (2006).

    CAS  PubMed  Google Scholar 

  12. Mullighan, C. G. et al. BCR–ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453, 110–114 (2008).

    Article  CAS  Google Scholar 

  13. Radich, J. P. et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc. Natl Acad. Sci. USA 8, 2794–2799 (2006).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Michigan, Internal Medicine – Hematology Oncology, 1,500 East Medical Center Drive, Ann Arbor, 48109-5936, Michigan, USA

    Michael Savona & Moshe Talpaz

Authors
  1. Michael Savona
    View author publications

    Search author on:PubMed Google Scholar

  2. Moshe Talpaz
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to Michael Savona or Moshe Talpaz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Savona, M., Talpaz, M. Cell-cycle deregulation in progressive CML. Nat Rev Cancer 8, 563 (2008). https://doi.org/10.1038/nrc2368-c2

Download citation

  • Issue date:

  • DOI: https://doi.org/10.1038/nrc2368-c2

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing