A novel pre-B acute lymphoblastic leukemia cell line with chromosomal translocation between p16(INK4A)/p15(INK4B) tumor suppressor and immunoglobulin heavy chain genes: TGFbeta/IL-7 inhibitory signaling mechanism.
p16 INK4A and/or p15 INK4B genes are frequently deleted in leukemias and other cancers. We have established a novel pre-B acute lymphoblastic leukemia (ALL) cell line (JKB2) with a chromosomal translocation between 9p2l and 14q32, on which p16INK4A/p15INK4B and heavy chain immunoglobulin (Ig) genes, respectively, are located. Homozygous deletions of P16INK4A/p15INK4B genes in JKB2 cells were confirmed by polymerase chain reaction, and their protein products were not detectable by Western blotting. Therefore JKB2 is the first example of an immunoglobulin heavy chain translocation associated with deletions of these genes. In JKB2 cells, cyclin-dependent kinase(CDK)4 and CDK6 formed complexes with cyclin D, due to the lack of p16, triggering phosphorylation of retinoblastoma protein (pRB) and continuous cell proliferation. Moreover, the growth of JKB2 cells was partially inhibited by TGF beta or IL-7, accompanied by decreased CDK4 and CDK6 expression, increased p2l and p27 expression, decreased p27 binding to CDK4/CDK6, and increased binding of p27 to CDK2. In addition, IL-7 both inhibited proliferation and induced differentiation of JKB2 cells. These studies suggest that a t(9;14)(p21;q32) chromosomal translocation can result in deletion of both p16 INK4A and p15 INK4B genes in pre-B ALL, and that the JKB2 cell line therefore provides a model for the study of leukemogenesis related to abnormalities in chromosome 9p2l. Moreover, they suggest that TGF-beta can, suppress JKB2 cell growth in a p15-independent mechanism.
Urashima
M
M
Dana-Farber Cancer Institute and the Department of Medicine, Harvard Medical School, Boston, MA, USA.
Hoshi
Y
Y
Sugimoto
Y
Y
Kaihara
C
C
Matsuzaki
M
M
Chauhan
D
D
Ogata
A
A
Teoh
G
G
DeCaprio
J A
JA
Anderson
K C
KC
D000293:Adolescent; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000032:analysis; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005260:Female; D005803:Genes, Immunoglobulin; D016147:Genes, Tumor Suppressor; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D015851:Interleukin-7 / Q000494:pharmacology*; D008969:Molecular Sequence Data; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007143:Immunoglobulin Heavy Chains; D015851:Interleukin-7; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins