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High Erk-1 activation and Gadd45a expression as prognostic markers in high risk pediatric haemolymphoproliferative diseases.

D'Angelo V, Crisci S, Casale F, Addeo R, Giuliano M, Pota E, Finsinger P, Baldi A, Rondelli R, Abbruzzese A, Caraglia M, Indolfi P - J. Exp. Clin. Cancer Res. (2009)

Bottom Line: On univariate analysis, only Erk-1 phosphorylation status was found to be correlated with a significantly shorter 5-years DFS in all disease subgroups (p = 0.033) and the lowest DFS median in ALL/NHL subgroup (p = 0.04).Moreover, the simultaneous activation of multiple kinases, as we found for c-Jun and Erk-1 (r = 0.26; p = 0.025), might synergistically enhance survival and proliferation potential of leukemic cells.These results demonstrate an involvement of these proteins in survival of blast cells and, consequently, on relapse percentages of the different subgroups of patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Pediatric Oncology Service, Pediatric Department, F Fede, II University of Naples, Naples, Italy. velia.dangelo@unina2.it

ABSTRACT
Studies on activated cell-signaling pathways responsible for neoplastic transformation are numerous in solid tumors and in adult leukemias. Despite of positive results in the evolution of pediatric hematopoietic neoplasias, there are some high-risk subtypes at worse prognosis. The aim of this study was to asses the expression and activation status of crucial proteins involved in cell-signaling pathways in order to identify molecular alterations responsible for the proliferation and/or escape from apoptosis of leukemic blasts. The quantitative and qualitative expression and activation of Erk-1, c-Jun, Caspase8, and Gadd45a was analyzed, by immunocytochemical (ICC) and western blotting methods, in bone marrow blasts of 72 patients affected by acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (ALL) and stage IV non-Hodgkin Lymphoma (NHL). We found an upregulation of Erk-1, Caspase8, c-Jun, and Gadd45a proteins with a constitutive activation in 95.8%, 91.7%, 86.2%, 83.4% of analyzed specimens, respectively. It is worth noting that all AML patients showed an upregulation of all proteins studied and the high expression of GADD45a was associated to the lowest DFS median (p = 0.04). On univariate analysis, only Erk-1 phosphorylation status was found to be correlated with a significantly shorter 5-years DFS in all disease subgroups (p = 0.033) and the lowest DFS median in ALL/NHL subgroup (p = 0.04). Moreover, the simultaneous activation of multiple kinases, as we found for c-Jun and Erk-1 (r = 0.26; p = 0.025), might synergistically enhance survival and proliferation potential of leukemic cells. These results demonstrate an involvement of these proteins in survival of blast cells and, consequently, on relapse percentages of the different subgroups of patients.

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Representative ICC for JNK (A), pErk-1 (B), Gadd45a (C) and Caspase8 (D). (A) JNK nuclear immune-reactivity in positive bone marrow blasts. (B, C) pErk-1 and Gadd45a nuclear and cytoplasmic staining in blasts. (D) Caspase8 cytoplasmic immune-staining in bone marrow blasts. Arrows show positive red stained cells.
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Figure 1: Representative ICC for JNK (A), pErk-1 (B), Gadd45a (C) and Caspase8 (D). (A) JNK nuclear immune-reactivity in positive bone marrow blasts. (B, C) pErk-1 and Gadd45a nuclear and cytoplasmic staining in blasts. (D) Caspase8 cytoplasmic immune-staining in bone marrow blasts. Arrows show positive red stained cells.

Mentions: In details, 30 specimens showed low and 30 high Gadd45a expression levels (83.4%), while in 12 samples (16.6%) the protein was absent. Immune-reactivity, detected in the nuclei and cytoplasms of blasts, showed high or low staining intensity in 40/60 samples (66.7%) and 20/60 samples (33.3%), respectively (Figure 1A).


High Erk-1 activation and Gadd45a expression as prognostic markers in high risk pediatric haemolymphoproliferative diseases.

D'Angelo V, Crisci S, Casale F, Addeo R, Giuliano M, Pota E, Finsinger P, Baldi A, Rondelli R, Abbruzzese A, Caraglia M, Indolfi P - J. Exp. Clin. Cancer Res. (2009)

Representative ICC for JNK (A), pErk-1 (B), Gadd45a (C) and Caspase8 (D). (A) JNK nuclear immune-reactivity in positive bone marrow blasts. (B, C) pErk-1 and Gadd45a nuclear and cytoplasmic staining in blasts. (D) Caspase8 cytoplasmic immune-staining in bone marrow blasts. Arrows show positive red stained cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2664791&req=5

Figure 1: Representative ICC for JNK (A), pErk-1 (B), Gadd45a (C) and Caspase8 (D). (A) JNK nuclear immune-reactivity in positive bone marrow blasts. (B, C) pErk-1 and Gadd45a nuclear and cytoplasmic staining in blasts. (D) Caspase8 cytoplasmic immune-staining in bone marrow blasts. Arrows show positive red stained cells.
Mentions: In details, 30 specimens showed low and 30 high Gadd45a expression levels (83.4%), while in 12 samples (16.6%) the protein was absent. Immune-reactivity, detected in the nuclei and cytoplasms of blasts, showed high or low staining intensity in 40/60 samples (66.7%) and 20/60 samples (33.3%), respectively (Figure 1A).

Bottom Line: On univariate analysis, only Erk-1 phosphorylation status was found to be correlated with a significantly shorter 5-years DFS in all disease subgroups (p = 0.033) and the lowest DFS median in ALL/NHL subgroup (p = 0.04).Moreover, the simultaneous activation of multiple kinases, as we found for c-Jun and Erk-1 (r = 0.26; p = 0.025), might synergistically enhance survival and proliferation potential of leukemic cells.These results demonstrate an involvement of these proteins in survival of blast cells and, consequently, on relapse percentages of the different subgroups of patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Pediatric Oncology Service, Pediatric Department, F Fede, II University of Naples, Naples, Italy. velia.dangelo@unina2.it

ABSTRACT
Studies on activated cell-signaling pathways responsible for neoplastic transformation are numerous in solid tumors and in adult leukemias. Despite of positive results in the evolution of pediatric hematopoietic neoplasias, there are some high-risk subtypes at worse prognosis. The aim of this study was to asses the expression and activation status of crucial proteins involved in cell-signaling pathways in order to identify molecular alterations responsible for the proliferation and/or escape from apoptosis of leukemic blasts. The quantitative and qualitative expression and activation of Erk-1, c-Jun, Caspase8, and Gadd45a was analyzed, by immunocytochemical (ICC) and western blotting methods, in bone marrow blasts of 72 patients affected by acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (ALL) and stage IV non-Hodgkin Lymphoma (NHL). We found an upregulation of Erk-1, Caspase8, c-Jun, and Gadd45a proteins with a constitutive activation in 95.8%, 91.7%, 86.2%, 83.4% of analyzed specimens, respectively. It is worth noting that all AML patients showed an upregulation of all proteins studied and the high expression of GADD45a was associated to the lowest DFS median (p = 0.04). On univariate analysis, only Erk-1 phosphorylation status was found to be correlated with a significantly shorter 5-years DFS in all disease subgroups (p = 0.033) and the lowest DFS median in ALL/NHL subgroup (p = 0.04). Moreover, the simultaneous activation of multiple kinases, as we found for c-Jun and Erk-1 (r = 0.26; p = 0.025), might synergistically enhance survival and proliferation potential of leukemic cells. These results demonstrate an involvement of these proteins in survival of blast cells and, consequently, on relapse percentages of the different subgroups of patients.

Show MeSH
Related in: MedlinePlus