BCR–ABL and CDKN2A: a dropped connection

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 p16^INK4A is a bona fide cyclin-dependent kinase inhibitor, p14^ARF (p19^Arf in mice) is not, but instead regulates p53 tumour suppressor function through its interaction with MDM2 (Ref. 5). BCR–ABL induces p19^Arf 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.