The INK4-ARF (CDKN2A/B) locus in hematopoiesis and BCR-ABL-induced leukemias.
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 p15(INK4B), that maintain Rb in its active, hypophosphorylated form, and p14(ARF) (p19(Arf) in mice), that inhibits Mdm2 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 BCR-ABL 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.
Williams
R T
RT
Departments of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Sherr
C J
CJ
D000818:Animals; D049109:Cell Proliferation; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016313:Genes, abl; D019942:Genes, p16; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000473:pathology; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics
D050762:Cyclin-Dependent Kinase Inhibitor p15