Bcr–abl and cdkn2a: a dropped connection

Access through your institution Buy or subscribe In their recent Review of chronic myeloid leukamia (CML) stem cell biology (Savona, M. & Talpaz, M. Getting to the stem of chronic

myeloid leukemia. _Nature Rev. Cancer_ 8, 341–350)1, Savona and Talpaz focus their attention exclusively on deregulated self-renewal mechanisms in Philadelphia chromosome (Ph)+ hematopoietic

stem cells (HSCs) in chronic-phase CML and on the role of β-catenin abnormalities in granulocyte–macrophage progenitors in myeloid blast crisis. However, a review of genomic abnormalities

in lymphoid blast crisis provides insights into alternative mechanisms of progenitor self-renewal in BCR–ABL-driven diseases. Deletion of the _CDKN2A_ locus (encoding the _INK4A_ and _ARF_

tumour suppressor genes) frequently occurs in the progression of CML from chronic-phase to lymphoid, but not myeloid, blast crisis2, and a recent genome-wide analysis3 (published

concurrently with this CML review) has reinforced the conclusions of earlier studies. _INK4A_ and _ARF_ share common second and third exons, are translated in alternate reading frames, and

exhibit no sequence similarity4. Whereas p16INK4A is a _bona fide_ cyclin-dependent kinase inhibitor, p14ARF (p19Arf in mice) is not, but instead regulates p53 tumour suppressor function

through its interaction with MDM2 (Ref. 5). BCR–ABL induces p19Arf _in vivo_ to oppose tumour development, but the combination of BCR–ABL expression and _Arf_ inactivation is sufficient to

generate leukaemia-initiating cells in a murine model of Ph+ acute lymphocytic leukaemia6. Therefore, in BCR–ABL-driven lymphoid leukaemias — specifically, CML lymphoid blast crisis and Ph+

acute lymphocytic leukaemia — deletion of _INK4A_ and _ARF_ in committed Ph+ lymphoid blasts is expected to simultaneously disrupt both the RB and p53 tumour suppressor networks, thereby

facilitating leukaemia-initiating cell self-renewal and enhancing targeted therapeutic resistance _in vivo_. This is a preview of subscription content, access via your institution ACCESS

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institutional subscriptions * Read our FAQs * Contact customer support REFERENCES * Savona, M. & Talpaz, M. Getting to the stem of chronic myeloid leukemia. _Nature Rev. Cancer_ 8,

341–350 (2008). Article  CAS  Google Scholar  * Calabretta, B. & Perrotti, D. The biology of CML blast crisis. _Blood_ 103, 4010–4022 (2004). Article  CAS  Google Scholar  * 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  * Quelle, D. E. et al. Alternative

reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. _Cell_ 83, 993–1000 (1995). Article  CAS  Google Scholar  * Sherr, C.

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Cytokine-dependent imatinib resistance in mouse BCR–ABL+, _Arf_-null lymphoblastic leukemia. _Genes Dev._ 21, 2283–2287 (2007). Article  CAS  Google Scholar  Download references AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * Departments of Oncology and of Genetics & Tumor Cell Biology, Memphis, 38105, Tennessee, USA Richard T. Williams * Howard Hughes Medical Institute,

St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, 38105, Tennessee, USA Charles J. Sherr Authors * Richard T. Williams View author publications You can also

search for this author inPubMed Google Scholar * Charles J. Sherr View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to

Richard T. Williams. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Williams, R., Sherr, C. BCR–ABL and _CDKN2A_: a dropped connection. _Nat Rev Cancer_

8, 563 (2008). https://doi.org/10.1038/nrc2368-c1 Download citation * Issue Date: July 2008 * DOI: https://doi.org/10.1038/nrc2368-c1 SHARE THIS ARTICLE Anyone you share the following link

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