Cell surface expression of CD150 and CD180 receptors in chronic lymphocytic leukemia (CLL) associates with mutational IGHV status and favourable prognosis. Here we show a direct correlation between cell surface expression and colocalization of these receptors on CLL B cells. In the absence of CD150 and CD180 on the cell surface both receptors were expressed in the cytoplasm. The CD150 receptor was colocalized with markers of the endoplasmic reticulum, the Golgi apparatus and early endosomes. In contrast, CD180 was detected preferentially in early endosomes. Analysis of CD150 isoforms differential expression revealed that regardless of CD150 cell surface expression the mCD150 isoform with two ITSM signaling motifs was a predominant CD150 isoform in CLL B cells. The majority of CLL cases had significantly elevated expression level of the soluble sCD150, moreover CLL B cells secrete this isoform. CD150 or CD180 crosslinking on CLL B cells alone led to activation of Akt, mTORC1, ERK1/2, p38MAPK and JNK1/2 networks. Both CD150 and CD180 target the translation machinery through mTOR independent as well as mTOR dependent pathways. Moreover, both these receptors transmit pro-survival signals via Akt-mediated inhibition of GSK3β and FOXO1/FOXO3a. Unexpectedly, coligation CD150 and CD180 receptors on CLL B cells led to mutual inhibition of the Akt and MAPK pathways. While CD150 and CD180 coligation resulted in reduced phosphorylation of Akt, ERK1/2, c-Jun, RSK, p70S6K, S6RP, and 4E-BP; it led to complete blocking of mTOR and p38MAPK phosphorylation. At the same time coligation of CD150 and CD40 receptors did not result in Akt and MAPK inhibition. This suggests that combination of signals via CD150 and CD180 leads to blocking of pro-survival pathways that may be a restraining factor for neoplastic CLL B cells propagation in more than 50% of CLL cases where these receptors are coexpressed.

Background: Even 25 years after the Chernobyl catastrophe, the interpretation of the findings on leukemia risk among Chernobyl clean-up workers is still a point of much controversy. Precise diagnosis of the main types of hematopoietic malignancies according to FAB classification and new WHO classification may be helpful in estimating the relative contribution of the radiation factor to the overall incidence of such pathologies. Methods:The data on 295 consecutive cases of malignant tumors of hematopoietic and lymphoid tissues in Chernobyl clean-up workers diagnosed from 1996 to 2010 are given in comparison with the data of 2,697 consecutive patients other than clean-up workers of the same age group. For this study, a set of complex diagnostic techniques were used, including morphology, cytochemistry of bone marrow and peripheral blood cells, immunocytochemistry (APAAP, LSAB-AP) as well as the utilization of monoclonal antibodies to lineage specific and differentiation antigens of leukocytes.Results: All the main forms of tumors of hematopoietic and lymphoid tissues were diagnosed among clean-up workers under study in 10-25 years after the Chernobyl catastrophe including myelodysplastic syndromes (MDS), acute leukemias (ALL and AML), chronic myelogenous leukemia (CML) and other myeloproliferative neoplasms, chronic lymphocytic leukemia (B-CLL) and lymphoid neoplasms of B and T cell origin. Among 46 AML cases in clean-up workers, leukemia was preceded by MDS in seven patients. CML percentage tended to be higher in the group of patients representing clean-up workers (9.13% vs. 6.59%). B-CLL was a predominant form of hematopoietic malignancies in clean-up workers under study (26.10%). Nevertheless, the percentage of B-CLL in patients of clean-up workers group did not differ significantly from that in the non-exposed patients. The multiple myeloma percentage in our study was higher in the clean-up workers (6.46% vs. 4.00%). Conclusions:The verified diagnosis of tumors of hematopoietic and lymphoid tissues according to the up-to-date WHO classification could be prerequisite for further molecular genetics and analytical epidemiology study of leukemias that may be related to the Chernobyl catastrophe.

The studies of the recent decades posed the question of the association between radiation exposure and myelodysplastic syndromes (MDS). This association has been proved in secondary MDS originating upon exposure to chemotherapeutics and/or radiation therapy. The long-term study in Japanese atomic (A)-bomb survivors demonstrated the significant linear dose-response for MDS confirming the link between radiation exposure and this form of hematopoietic malignancies. All these findings provide the strong basis for studying MDS in the persons exposed to radiation following the Chernobyl disaster, especially those in the cohort of Chernobyl clean-up workers of 1986-1987. The data on MDS among Chernobyl clean-up workers (1986-1987) diagnosed in 1996-2012 at the reference laboratory of RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology are summarized. MDS cases were diagnosed in 23 persons (21 males and 2 females) having been exposed to radiation as clean-up workers of 1986-1987. Refractory anemia (RA) has been detected in 13, refractory anemia with ring sideroblasts (RARS)-in 2, and refractory anemia with excess blasts (RAEB)-in 8 patients. The median age of those MDS patients was 62.0 years. In addition, 5 cases of chronic myelomonocytic leukemia (CMML) were recorded in the group of Chernobyl clean-up workers with the median time of 14.8 years from 1986-1987 to diagnosis. The association between radiation exposure and MDS is discussed. The suggested life-long risk for myelodysplastic syndromes among A-bomb survivors in Japan highlights the importance of the continuing follow-up studies in the affected populations in the post-Chernobyl period.