Expression of ERK1/ERK2 MAP Kinase, Protein Kinase C and Akt Kinase by Lymphoid Malignant Cells.

ERK1/ERK2 MAP kinase (MAPK), protein kinase C (PKC) and Akt kinase have been shown to inhibit cellular apoptosis. We measured the expression levels of these protein kinases in a total of 102 samples from patients with lymphoid malignancies: 26 with acute lymphoblastic leukemia (ALL), 15 with multiple myeloma (MM), 49 with non-Hodgkin’s lymphoma (NHL), 3 with Hodgkin’s lymphoma (HL) and 6 with chronic lymphocytic leukemia (CLL). Plasma cells were separated by using magnetically labeled CD138, and the purity of the cells were more than 95%. The MAPK and PKC assay systems are based upon the enzyme catalyzed transfer of the [γ-³²P] ATP to a specific peptide. Activity of Akt kinase was measured by Western blotting using phospho-specific Akt (Ser 473) antibody. MAPK activity was 0.4±0.0, 4.7±0.7 and 19.0±21.6 p mol/min/10⁶ cells in normal blood mononuclear cells (n=3), normal bone marrow plasma cells (n=10), and patient samples (n=85), respectively. MAPK and PKC activities were 17.1±10.5 and 50.7±58.3 p mol/min/10⁶ cells in ALL, 29.3±39.3 and 29.1±18.9 in MM, 17.3±16.4 and 46.5±46.7 in NHL, 13.6±3.2 and 4.0±3.2 in HL, and 7.3±4.8 and 2.2±0.2 in CLL, respectively. MAPK activity of CLL was significantly low (P<0.05) compared with that of ALL. Phosphorylated Akt was detected in 57 of 59 (97%) patients examined. A significant positive correlation between the activities of PKC and Akt kinase, but not those of MAPK and PKC or MAPK and Akt kinase, was noted. Kaplan-Meier estimates of overall survival (OS) revealed that the OS of the MM patients with lower MAPK was better than those with higher MAPK, although the difference was not significant (P = 0.15). OS was not different by MAPK for ALL or NHL, and by PKC for ALL, MM, or NHL. Effects of various cytokines on the MAPK activity of malignant lymphoid cells in serum free culture were examined. IL-7 significantly enhanced the MAPK activity in 46% of ALL patients, IL-15 in 31% of NHL patients, and IL-15 and IL-6 in 38% and 35% of MM patients, respectively. Taken together, our results suggest that MAPK activity is significantly and markedly elevated and that MAPK may play important roles by various subtype of lymphoid malignancies.