The INK4-ARF (CDKN2A/B) locus in hematopoiesis and BCR-ABL-induced leukemias

Abstract

Senescence and apoptosis programs governed by the Rb and p53 signaling networks can counter tissue stem cell self-renewal. A master regulator of Rb and p53 is the INK4-ARF (CDKN2A/B) locus that encodes two CDK inhibitors, p16 INK4A and p15INK4B, that maintain Rb in its active, hypophosphorylated form, and p14ARF (p19Arf in mice), that inhibitsMdm2 and activates p53. The INK4-ARF genes are epigenetically silenced in hematopoietic stem cells but become poised to respond to oncogenic stress as blood cells differentiate. Inactivation of INK4-ARF endows differentiated cells with an inappropriate self-renewal capacity, a defining feature of cancer cells. In BCR-ABL-induced (Philadelphia chromosome-positive [Ph+]) leukemias, INK4-ARF deletions frequently occur in clinically aggressive acute lymphoblastic leukemias (Ph+ ALLs) but are not seen in more indolent Ph+ chronic myelogenous leukemia (CML) or in CML myeloid blast crisis. Mouse modeling of Ph+ ALL reveals that Arf inactivation attenuates responsiveness to targeted BCR-ABL kinase inhibitors, enhances the maintenance of leukemia-initiating cells within the hematopoietic microenvironment, and facilitates the emergence of malignant clones that harbor drug-resistant BCRABL kinase mutations. Thus, although BCR-ABL mutations typify drug resistance in both CML and Ph+ ALL, loss of INK4-ARF in Ph + ALL enhances disease aggressiveness and undermines the salutary effects of targeted therapy. ©2008 Cold Spring Harbor Laboratory Press.