Ætiology of Leukæmia

Nowell̀, Peter C.; Hungerford, David A.

doi:10.1016/s0140-6736(60)92932-9

Cited by 33 publications

(26 citation statements)

References 2 publications

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“…Previous studies have shown that several immediate-early genes are induced by BCR/ABL, including myc (22), fos, and jun (23). The rapid induction of these genes correlates with an enhanced rate of transition from G 0 to G 1 . The increased fraction of cells in S phase suggests that G 1 /S transition checkpoints are also suppressed.…”

Section: Chronic Myelogenous Leukemia (Cml)mentioning

confidence: 99%

BCR/ABL Regulates Expression of the Cyclin-dependent Kinase Inhibitor p27Kip1 through the Phosphatidylinositol 3-Kinase/AKT Pathway

Gesbert¹,

Sellers²,

Signoretti³

et al. 2000

Journal of Biological Chemistry

206

147

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Deregulation of cell cycle checkpoints is an almost universal abnormality in human cancers and is most often due to loss-of-function mutations of tumor suppressor genes such as Rb, p53, or p16INK4a . In this study, we demonstrate that BCR/ABL inhibits the expression of a key cell cycle inhibitor, p27 Kip1 , by signaling through a pathway involving phosphatidylinositol 3-kinase (PI3K). p27Kip1 is a widely expressed inhibitor of cdk2, an essential cell cycle kinase regulating entry into S phase. We demonstrate that the decrease of p27Kip1 is directly due to BCR/ABL in hematopoietic cells by two different approaches. First, induction of BCR/ABL by a tetracycline-regulated promoter is associated with a reversible down-regulation of p27 Kip1 . Second, inhibition of BCR/ABL kinase activity with the Abl tyrosine kinase inhibitor STI571 rapidly increases p27Kip1 levels. The PI3K inhibitor LY-294002 blocks the ability of BCR/ABL to induce p27 Kip1 down-regulation and inhibits BCR/ ABL-induced entry into S phase. The serine/threonine kinase AKT/protein kinase B is a known downstream target of PI3K. Transient expression of an activated mutant of AKT was found to decrease expression of p27 Kip1, even when PI3K was inhibited by LY-294002. The mechanism of p27 Kip1 regulation is primarily related to protein stability, since inhibition of proteasome activity increased p27 Kip1 levels in BCR/ABL-transformed cells, whereas very little change in p27 transcription was found. Overall, these data are consistent with a model in which BCR/ABL suppresses p27Kip1 protein levels through PI3K/AKT, leading to accelerated entry into S phase. This activity is likely to explain in part previous studies showing that activation of PI3K was required for optimum transformation of hematopoietic cells by BCR/ABL in vitro and in vivo.

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Section: Chronic Myelogenous Leukemia (Cml)mentioning

confidence: 99%

BCR/ABL Regulates Expression of the Cyclin-dependent Kinase Inhibitor p27Kip1 through the Phosphatidylinositol 3-Kinase/AKT Pathway

Gesbert¹,

Sellers²,

Signoretti³

et al. 2000

Journal of Biological Chemistry

206

147

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“…he Philadelphia chromosome (Ph) (1), arising from a balanced translocation involving chromosomes 9 and 22 (2), is the founding genetic lesion and cytogenetic hallmark of chronic myelogenous leukemia (CML) and of a subset of Ph ϩ acute lymphoblastic leukemias (ALLs). These translocations fuse a breakpoint cluster region (BCR) derived from chromosome 22 to a portion of the c-ABL protooncogene from chromosome 9, thereby leading to formation of alternative BCR-ABL fusion proteins p210…”

mentioning

confidence: 99%

Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia

Williams¹,

Roussel²,

Sherr

2006

Proc. Natl. Acad. Sci. U.S.A.

179

206

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“…A notable exception is chronic myelogenous leukemia (CML), 1 which is highly resistant to most commonly utilized chemotherapeutic drugs, including taxol (4,5). CML cells, such as K562 cells, are characterized by the presence of the Philadelphia chromosome, which results from a reciprocal translocation involving chromosome 9 and chromosome 22 (6,7). In K562 cells, the Abl tyrosine kinase gene on chromosome 9 is translocated into the breakpoint cluster region (bcr) region on chromosome 22 producing a chimeric gene whose product, Bcr-Abl, expresses disregulated Abl tyrosine kinase activity (8).…”

mentioning

confidence: 99%

Protein Kinase Cι Activity Is Necessary for Bcr-Abl-mediated Resistance to Drug-induced Apoptosis

Jamieson

Carpenter

Biden

et al. 1999

Journal of Biological Chemistry

107

128

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Ætiology of Leukæmia

Cited by 33 publications

References 2 publications

BCR/ABL Regulates Expression of the Cyclin-dependent Kinase Inhibitor p27Kip1 through the Phosphatidylinositol 3-Kinase/AKT Pathway

BCR/ABL Regulates Expression of the Cyclin-dependent Kinase Inhibitor p27Kip1 through the Phosphatidylinositol 3-Kinase/AKT Pathway

Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia

Protein Kinase Cι Activity Is Necessary for Bcr-Abl-mediated Resistance to Drug-induced Apoptosis

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