Notch3-mediated regulation of MKP-1 levels promotes survival of T acute lymphoblastic leukemia cells

Masiero, Massimo; Minuzzo, Sonia; Pusceddu, Irene; Moserle, Lidia; Persano, Luca; Agnusdei, Valentina; Tosello, Valeria; Basso, Giuseppe; Amadori, Alberto; Indraccolo, Stefano

doi:10.1038/leu.2010.323

Cited by 48 publications

(32 citation statements)

References 42 publications

(68 reference statements)

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“…47 Among the various components of the NOTCH pathway, the activation of NOTCH3 was reported in epithelial ovarian cancer, extrahepatic cholangiocarcinoma, gallbladder cancer, and T-acute lymphoblastic leukemia. 23,48,49 We found 50% of colorectal cancer expressed NOTCH3. Compared with non-micropapillary carcinoma, cases with micropapillary carcinoma showed significantly higher levels of NOTCH3 expression (42 vs 69%).…”

Section: Modern Pathology (2013) 26 1123-1131mentioning

confidence: 81%

Colorectal micropapillary carcinomas are associated with poor prognosis and enriched in markers of stem cells

et al. 2013

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Colorectal micropapillary carcinoma has recently been reported as an aggressive variant of adenocarcinoma with a high incidence of lymph node metastasis, but has not been well investigated in terms of survival analysis. This study analyzed the clinicopathological characteristics, including survival data, of the patients with micropapillary carcinoma. We hypothesized that the aggressive features of micropapillary carcinoma might be related to the presence of more tumor cells with stem cell phenotype in colorectal cancer. Fifty-five (10%) micropapillary carcinoma cases were identified among 561 cases of colorectal cancer. We compared the clinicopathological characteristics, including survival data and immunohistochemical profiles of stem cell markers (SOX2, NOTCH3, CD44v6, CD166, ALDH1) of micropapillary carcinomas with those of randomly selected 112 conventional adenocarcinomas lacking micropapillary carcinoma components (non-micropapillary carcinoma) in the colorectum. To exclude the possibility of dilution of control group by patients with microsatellite instability-high carcinomas, we divided non-micropapillary carcinomas into microsatellite instability-high carcinoma and microsatellite stable tumors. Micropapillary carcinomas were characterized by more frequent lymphovascular invasion (Po0.0001) and lymph node metastasis (Po0.0001), higher pathological T and tumor node metastasis stages (P ¼ 0.047 and P ¼ 0.001), and more frequent SOX2 (P ¼ 0.038) and NOTCH3 expressions (P ¼ 0.005). Overall 5-year survival rate for patients with micropapillary carcinoma (37%) was significantly lower than for microsatellite instability-high carcinoma and microsatellite stable carcinoma patients (92 and 72%, Po0.0001). The presence of the micropapillary carcinoma component was shown to be associated with a significantly worse survival rate in univariate (Po0.0001) and multivariate (P ¼ 0.003, Cox hazard ratio 2.402) analyses. In conclusion, recognition of the micropapillary carcinoma component in colonic adenocarcinoma is very important, because the micropapillary carcinoma has been associated with a significantly worse prognosis. We also found a higher expression rate of cancer stem cell markers in micropapillary carcinomas, suggesting their potential contribution to the survival disadvantage of micropapillary carcinoma. Modern Pathology (2013Pathology ( ) 26, 1123Pathology ( -1131 doi:10.1038/modpathol.2012 published online 12 October 2012 Keywords: colorectum; micropapillary carcinoma; prognosis; stem cell marker; TNM stage Colorectal cancer is one of the leading causes of cancer deaths worldwide, and both the prevalence and the incidence rate in South Korea are rapidly rising. 1 For metastatic colorectal cancer, the 5-year survival rate is only about 10%. 2 Micropapillary carcinoma is a relatively uncommon and distinctive tumor characterized by small clusters of tumor cells in the clear lacunar spaces, mimicking lymphatic or vascular channels. 3 Micropapillary carcinoma has high potential to metastasize to the regional l...

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Section: Modern Pathology (2013) 26 1123-1131mentioning

confidence: 81%

Colorectal micropapillary carcinomas are associated with poor prognosis and enriched in markers of stem cells

et al. 2013

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“…55 Furthermore, maintenance of high ERK in conjunction with other MAPK pathways is required for the quiescence of T-ALL cells. 56 JNK is also associated with survival signaling in acute leukemias, for example, by upregulating antiapoptotic genes in AML stem cells. 57 Furthermore, the JNK-JunD pathway cooperates with NF-kB causing cell survival.…”

Section: Discussionmentioning

confidence: 99%

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)

Krause¹,

Pfeiffer²,

Strube³

et al. 2015

Blood

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Key Points• Mer mediates quiescence and chemotherapy resistance in a CNS coculture model and causes CNS infiltration in immunodeficient mice.• Mer expression correlates with CNS positivity upon initial diagnosis in t(1;19)-positive pediatric ALL patients.Patients with t(1;19)-positive acute lymphoblastic leukemia (ALL) are prone to central nervous system (CNS) relapses, and expression of the TAM (Tyro3, Axl, and Mer) receptor Mer is upregulated in these leukemias. We examined the functional role of Mer in the CNS in preclinical models and performed correlative studies in 64 t(1;19)-positive and 93 control pediatric ALL patients. ALL cells were analyzed in coculture with human glioma cells and normal rat astrocytes: CNS coculture caused quiescence and protection from methotrexate toxicity in Mer high ALL cell lines, which was antagonized by short hairpin RNA-mediated knockdown of Mer. Mer expression was upregulated, prosurvival Akt and mitogen-activated protein kinase signaling were activated, and secretion of the Mer ligand Galectin-3 was stimulated. Mer high t(1;19) primary cells caused CNS involvement to a larger extent in murine xenografts than in their Mer low counterparts.Leukemic cells from Mer high xenografts showed enhanced survival in coculture.Treatment of Mer high patient cells with the Mer-specific inhibitor UNC-569 in vivo delayed leukemia onset, reduced CNS infiltration, and prolonged survival of mice. Finally, a correlation between high Mer expression and CNS positivity upon initial diagnosis was observed in t(1;19) patients. Our data provide evidence that Mer is associated with survival in the CNS in t(1;19)-positive ALL, suggesting a role as a diagnostic marker and therapeutic target. (Blood. 2015;125(5):820-830) Introduction TAM (Tyro3, Axl, and Mer) receptors have been advocated as therapeutic targets in human cancers including leukemia. 1-3 The TAM receptor family consists of Tyro3, Axl, and Mer 4 which all have been found to have transforming properties. [5][6][7] Mer expression has been shown on macrophages, natural killer (NK) cells, dendritic cells, megakaryocytes, and platelets, 8 but it is not known to be present on normal T and B lymphocytes at any stage of differentiation. Aberrant Mer expression was detected in not only acute myeloid leukemia (AML), 9 but also lymphocytic malignancies as T-cell acute lymphoblastic leukemia (T-ALL).10 Studies overexpressing Mer in fibroblasts found that it can induce extracellular signalregulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, nuclear factor-kB (NF-kB) and enhance cell survival via phosphatidylinositol 3-kinase (PI3K)/AKT. 2,11 Linger et al 12 reported that Mer is overexpressed on pre-B-cell ALL (B-ALL) cells of pediatric patients with t(1;19)(q23;p13) translocation. Furthermore, inhibition of Mer by RNA interference (RNAi) reduced survival and chemoresistance of pre-B-ALL cell lines and prolonged survival of xenografts.12 Pediatric ALL with t(1;19)(q23;p13) translocation is found in about 3% to 5% of ALL patients and has ...

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“…[1][2][3][4][5] Survival rates at 5 years for children and adolescents with T-ALL are 70-75%, whereas for adults the rates are 35-40%. 6,7 Therefore, there is a need for novel and less toxic treatment strategies targeting aberrantly activated signaling pathways that increase proliferation, survival and drug resistance of T-ALL cells.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

et al. 2012

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Notch3-mediated regulation of MKP-1 levels promotes survival of T acute lymphoblastic leukemia cells

Cited by 48 publications

References 42 publications

Colorectal micropapillary carcinomas are associated with poor prognosis and enriched in markers of stem cells

Colorectal micropapillary carcinomas are associated with poor prognosis and enriched in markers of stem cells

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

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