Cellular Signalling Pathways: New Targets in Leukaemia Therapy

Ravandi, Farhad; Talpaz, Moshe; Kantarjian, Hagop; Estrov, Zeev

doi:10.1046/j.1365-2141.2002.03236.x

Cited by 25 publications

(30 citation statements)

References 211 publications

(273 reference statements)

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“…2 The BCR-ABL tyrosine kinase inhibitor STI571 (Imatinib mesylate) has significant antileukemic activity in patients with CML. 63 Piceatannol, which is known as a Sykselective tyrosine kinase inhibitor, 64,65 suppressed the survival and proliferation of TEL-Syk-transformed BaF3 cells and inhibited the phosphorylation of STAT5, but piceatannol also suppressed IL-3-induced BaF3 cell growth (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways

et al. 2004

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We previously reported the fusion of the TEL gene to the Syk gene in myelodysplastic syndrome with t(9;12)(q22;p12). TELSyk fusion transformed interleukin-3 (IL-3)-dependent murine hematopoietic cell line BaF3 to growth factor independence. Here, we investigate the intracellular signal transduction of the stable transfectants. TEL-Syk fusion protein was associated with the p85 subunit of phosphatidyl inositol 3 kinase (PI3-K) followed by the activation of Akt in the absence of IL-3. Vav, phospholipase C-c2 and mitogen-activated protein kinase (MAPK) were also constitutively activated. TEL-Syk also activated the signal transducer and activator of transcription 5 (STAT5) in the absence of Janus kinase 2 activation. None of these kinases were phosphorylated in the BaF3 cells transfected with TELDPNT-Syk in which the oligomerization domain of TEL was deleted. Inhibitor analysis showed that the MAPK pathway was important in TEL-Syk-mediated cell proliferation. The immunofluorescence technique revealed that the TEL-Syk fusion protein was located in the cytoplasm. These data suggest that TEL-Syk fusion protein in the cytoplasm leads to the constitutive activation of PI3-K/Akt, MAPK and STAT5 signal pathways, which are closely involved in IL-3-independent cell proliferation of BaF3 cells.

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Section: Discussionmentioning

confidence: 99%

“…The deregulation of their signaling plays a significant role in the malignant transformation of hematological disorders. 1,2 Syk is a nonreceptor tyrosine kinase that is widely expressed in a variety of hematopoietic cells. In the B-lineage lymphoid cell, Syk is a key regulator of signal transduction and differentiation.…”

Section: Introductionmentioning

confidence: 99%

TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways

et al. 2004

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“…These MAP kinase pathways are involved in cell survival (ERK and JNK) and cell death (p38 MAPK) and have been reported to play critical roles in the pathogenesis of various hematologic malignancies. 31,32 Miller et al 33 recently showed that pharmacologic inhibition of ERK and JNK enhanced glucocorticoidinduced apoptosis, whereas inhibition of p38 MAPK activity opposed glucocorticoid-induced apoptosis in lymphoid cells. Four genes (DUSP1, DUSP10, DSIPI [alias GILZ], and SGK) that we found to be induced on prednisolone exposure are negative regulators of the MAP kinase pathways.…”

Section: Signal Transduction Pathways Possibly Involved In Glucocortimentioning

confidence: 99%

Genomewide identification of prednisolone-responsive genes in acute lymphoblastic leukemia cells

Tissing

Boer

Meijerink

et al. 2007

Blood

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Glucocorticoids are keystone drugs in the treatment of childhood acute lymphoblastic leukemia (ALL). To get more insight in signal transduction pathways involved in glucocorticoid-induced apoptosis, Affymetrix U133A GeneChips were used to identify transcriptionally regulated genes on 3 and 8 hours of prednisolone exposure in leukemic cells of 13 children as compared with nonexposed cells. Following 3 hours of exposure no significant changes in gene expression could be identified. Following 8 hours of exposure, 51 genes were differentially expressed (P < .001 and false discovery rate < 10%) with 39 genes being up-regulated (median, 2.4-fold) and 12 genes were downregulated (median, 1.7-fold). Twenty-one of those genes have not been identified before to be transcriptionally regulated by prednisolone. Two of the 3 most highly up-regulated genes were tumor suppressor genes, that is, thioredoxin-interacting protein (TXNIP; 3.7-fold) and zinc finger and BTB domain containing 16 (ZBTB16; 8.8-fold). About 50% of the differentially expressed genes were functionally categorized in 3 major routes, namely MAPK pathways (9 genes), NF-B signaling (

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“…It is widely known that the survival and proliferation of leukemic cells are facilitated by an interactive network of signaling pathways (7). Studies on solid tumors provide evidence that the disruption of one or two members of this network may not be enough to completely abrogate the malig-nant phenotype (8).…”

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confidence: 99%

Effects of 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) on Pediatric Acute Lymphoblastic Leukemia (ALL) with Respect to Bcr-Abl Status and Imatinib Mesylate Sensitivity

2005

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As more and more effective targeted therapeutics have been developed to treat adults with cancer, it is of critical importance to devise appropriate in vitro experimental models to study their use in pediatric patients. Acute lymphoblastic leukemia (ALL) with Bcr-Abl translocation is one of the most difficult to treat and deadly diseases in children. The targeted kinase inhibitor imatinib mesylate has been shown to induce an initial response but resistance often develops. Recently, the geldanamycin family of antibiotics has been found to induce apoptosis in many malignant cells, including adult CML and AML. We describe experiments in which 17-allylamino-17-demethoxygeldanamycin (17-AAG) was evaluated in the context of Bcr-Abl and resistance to imatinib mesylate. Pediatric ALL cell lines with varying Bcr-Abl status and imatinib mesylate sensitivity were generated and their growth inhibition by 17-AAG was studied in vitro. Western blots were used to follow the changes in proteins that correlate with cell survival. Results show that apoptosis was induced in all lines with an increased 50% inhibitory concentration (IC 50 ) for BcrAbl positive but imatinib mesylate-resistant cells. Addition of 17-AAG greatly increased imatinib sensitivity in vitro. A decrease in p53, survivin, Her2/neu, and WT1 was seen in cells that expressed these proteins. With some notable exceptions, when combined with 17-AAG, the IC 50 of most of the common chemotherapeutic agents decreased. We describe an experimental approach to investigate the complex interaction between Bcr-Abl status, imatinib mesylate sensitivity, and 17-AAG in pediatric ALL. Information from such an approach will provide means to devise combined treatment approaches and to follow their effectiveness in vitro. Despite the impressive therapeutic advances of the last 30 years, a quarter of the children with ALL still die from their disease (1). Attempts to cure the patients at greatest risk of treatment failure have included intensification of chemotherapeutic regimens and the use of bone marrow transplantation. In recent years, an increasing knowledge of the molecular mechanisms involved in leukemic cell growth has shifted the focus of new antileukemic drug development from empirical antineoplastics to agents that act on specific molecular targets. Such targets include individual proteins that regulate signal transduction, apoptosis, and cell cycle progression and those that confer oncogenic potential such as Bcr-Abl (2).The Philadelphia chromosome is a product of a t(9;22)(q34;q11) translocation that fuses the c-Abl gene on chromosome 9 with the Bcr gene on chromosome 22 (3). This abnormality is observed in 3-5% of children with ALL, and it is one of the most difficult to treat among all childhood leukemias (1,4). The use of the novel kinase inhibitor imatinib mesylate (Gleevec, STI571; Novartis, Basel, Switzerland) has shown effectiveness in relapsed Phϩ ALL (5), but adult studies have shown significant potential for recurrence (6).It is widely known that the survival an...

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Cellular Signalling Pathways: New Targets in Leukaemia Therapy

Cited by 25 publications

References 211 publications

TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways

TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways

Genomewide identification of prednisolone-responsive genes in acute lymphoblastic leukemia cells

Effects of 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) on Pediatric Acute Lymphoblastic Leukemia (ALL) with Respect to Bcr-Abl Status and Imatinib Mesylate Sensitivity

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