title: Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor.
abstract: The cell of origin of tumors and the factors determining the cell of origin remain unclear. In this study, a mouse model of precursor B acute lymphoblastic leukemia/lymphoma (pre-B ALL/LBL) was established by retroviral transduction of Myc genes (N-Myc or c-Myc) into mouse bone marrow cells. Hematopoietic stem cells (HSCs) exhibited the highest susceptibility to N-Myc-induced pre-B ALL/LBL versus lymphoid progenitors, myeloid progenitors and committed progenitor B cells. N-Myc was able to induce pre-B ALL/LBL directly from progenitor B cells in the absence of Ink4a and Arf. Arf was expressed higher in progenitor B cells than Ink4a. In addition, N-Myc induced pre-B ALL/LBL from Arf(-/-) progenitor B cells suggesting that Arf has a predominant role in determining the cell of origin of pre-B ALL/LBL. Tumor cells derived from Ink4a/Arf(-/-) progenitor B cells exhibited a higher rate of proliferation and were more chemoresistant than those derived from wild-type HSCs. Furthermore, the Mdm2 inhibitor Nutlin-3 restored p53 and induced massive apoptosis in mouse pre-B ALL/LBL cells derived from Ink4a/Arf(-/-) cells and human B-ALL cell lines lacking Ink4a and Arf expression, suggesting that Mdm2 inhibition may be a novel therapeutic approach to the treatment of Ink4a/Arf(-/-) B-ALL/LBL, such as is frequently found in Ph(+) ALL and relapsed ALL. Collectively, these findings indicate that Ink4a and Arf are critical determining factors of the cell of origin and the therapeutic sensitivity of Myc-induced lymphoid tumors.
authors: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
authors: E
authors: E
authors: Sugihara
authors: T
authors: T
authors: Shimizu
authors: K
authors: K
authors: Kojima
authors: N
authors: N
authors: Onishi
authors: K
authors: K
authors: Kai
authors: J
authors: J
authors: Ishizawa
authors: K
authors: K
authors: Nagata
authors: N
authors: N
authors: Hashimoto
authors: H
authors: H
authors: Honda
authors: M
authors: M
authors: Kanno
authors: M
authors: M
authors: Miwa
authors: S
authors: S
authors: Okada
authors: M
authors: M
authors: Andreeff
authors: H
authors: H
authors: Saya
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D003561:Cytarabine / Q000494:pharmacology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016259:Genes, myc; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007093:Imidazoles; D010879:Piperazines; D025803:Tumor Suppressor Protein p14ARF; D003561:Cytarabine; C482205:nutlin 3