JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis

Steelman, Linda S.; Pohnert, Steven C.; Shelton, John G.; Franklin, Richard A.; Bertrand, F. E.; McCubrey, James A.

doi:10.1038/sj.leu.2403241

Cited by 621 publications

(538 citation statements)

References 423 publications

(536 reference statements)

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“…These observations suggest that alternative mechanisms of activation exist for these signaling molecules in HA-CML cells. 33 In addition to the phosphorylation status of Bcr-Abl, the sensitivity to antileukemic agents depends on the balance of pro-and antiapoptotic molecules. 8 Akt pro-survival effects have been reported to be dependent on the first step in glycolysis.…”

Section: Discussionmentioning

confidence: 99%

Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment

et al. 2010

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Abl tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib are ineffective against Bcr-Abl þ leukemic stem cells. Thus, the identification of novel agents that are effective in eradicating quiescent Bcr-Abl þ stem cells is needed to cure leukemias caused by Bcr-Abl þ cells. Human Bcr-Abl þ cells engrafted in the bone marrow of immunodeficient mice survive under severe hypoxia. We generated two hypoxia-adapted (HA)-Bcr-Abl þ sublines by selection in long-term hypoxic cultures (1.0% O 2 ). Interestingly, HA-Bcr-Abl þ cells exhibited stem cell-like characteristics, including more cells in a dormant, increase of side population fraction, higher b-catenin expression, resistance to Abl TKIs, and a higher transplantation efficiency. Compared with the respective parental cells, HA-Bcr-Abl þ cells had higher levels of protein and higher enzyme activity of glyoxalase-I (Glo-I), an enzyme that detoxifies methylglyoxal, a cytotoxic by-product of glycolysis. In contrast to Abl TKIs, Glo-I inhibitors were much more effective in killing HA-Bcr-Abl þ cells both in vitro and in vivo. These findings indicate that Glo-I is a novel molecular target for treatment of Bcr-Abl þ leukemias, and, in particular, Abl TKI-resistant quiescent Bcr-Abl þ leukemic cells that have acquired stem-like characteristics in the process of adapting to a hypoxic environment.

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Section: Discussionmentioning

confidence: 99%

Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment

et al. 2010

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“…These data indicated that BCR/ABL could upregulate SPK1 expression and increase its cellular activity in CML cells. It is known that BCR/ABL activates several signals, including mitogen-activated protein kinase, Janus kinase 2 (JAK2) and phosphoinositide 3-kinase (PI3K) in CML cells (Cortez et al, 1996;Skorski et al, 1997;Sillaber et al, 2000;Steelman et al, 2004;Samanta et al, 2006). To examine the roles of these signals in SPK1 expression induced by BCR/ABL in CML cells, the bcr-abl-transformed BaF3 cells, BaF3/pLXSN and K562 cells were pretreated with PD98059, Wortmannin and AG490, specific inhibitors of extracellular signal-regulated kinase 1/2, PI3K and JAK2, respectively, and then the BCR/ABL-induced SPK1 activity and expression were assayed.…”

mentioning

confidence: 99%

Sphingosine kinase-1 mediates BCR/ABL-induced upregulation of Mcl-1 in chronic myeloid leukemia cells

Qf¹,

Hf³

et al. 2007

Oncogene

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The signaling mechanisms responsible for BCR/ABLinduced regulation of Mcl-1 expression in chronic myelogenous leukemia (CML) cells remain unclear. In this study, we show that BCR/ABL could upregulate sphingosine kinase-1 (SPK1) expression via multiple signal pathways, including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) and Janus kinase 2 (JAK2), leading to increase cellular SPK1 activity in CML cells.

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“…Such a tyrosine kinase activates the Ras/Raf/MEK/ERK and JAK/STAT signal transduction pathways, and this results in an amplified proliferative state [22]. Bcr-Abl causes hyperactivity of Ras, Raf and JAK/STAT, which can occur by multiple mechanisms; i.e., by Bcr-Abl activating these pathways directly, or by the induction of autocrine cytokines, which in turn activate these pathways [23].…”

Section: Proliferationmentioning

confidence: 99%

“…Two other adapter molecules, Shc and Crkl, can also activate Ras [9,24]. Ras activates Raf, and finally, Raf initiates a signaling cascade through the serine-threonine kinases Mek1/ Mek2 and Erk, which ultimately leads to the transcription of genes involved in cell proliferation and survival (Figure 1), such as c-Myc, Cyclin D, Cyclin A, Bcl-2, cytokines, etc [22].…”

Section: Proliferationmentioning

confidence: 99%

Hematopoietic Stem Cells in Chronic Myeloid Leukemia

Chávez‐González¹,

Avilés-Vázquez²,

DafneMoreno-Lorenzana³

et al. 2013

Stem Cell Biology in Normal Life and Diseases

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JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis

Cited by 621 publications

References 423 publications

Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment

Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment

Sphingosine kinase-1 mediates BCR/ABL-induced upregulation of Mcl-1 in chronic myeloid leukemia cells

Hematopoietic Stem Cells in Chronic Myeloid Leukemia

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