ACUTE LEUKEMIAS IN CHILDREN FROM THE CITY OF KIEV AND KIEV REGION AFTER THE CHERNOBYL NPP CATASTROPHE

During 1993-1997, 247 cases of childhood acute leukemia (AL) were analyzed among inhabitants of the city of Kiev and Kiev region, excluding the most contaminated areas belonging to the strict control zone. The criteria of an FAB classification supplemented by immunophenotyping data were applied. The AL pattern was shown to be quite typical except for several peculiar features characteristic of this regional group of patients, especially the absence of age peaks in children with acute myelogenous leukemias (AML), increased frequency of the T1 variant in T-cell acute lymphoblastic leukemia (ALL), and higher levels of M4 and M5 variants in AML. A typical variant of M5a-AML with minimal signs of differentiation was found.     

DNA Repair Polymorphisms in B-cell Chronic Lymphocytic Leukemia in Sufferers of Chernobyl Nuclear Power Plant Accident

An association between DNA repair gene polymorphisms, environmental factors, and development of some types of cancer has been suggested by several studies. Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the clean-up workers of the Chernobyl Nuclear Power Plant (NPP) accident and it has some specific features. Therefore, we have studied the possible differences in DNA repair gene polymorphisms in CLL patients depending on ionizing radiation (IR) exposure history and their clinical characterictics. Arg399Gln XRCC1, Thr241Met XRCC3, and Lys751Gln XPD polymorphisms were studied in 64 CLL patients, exposed to IR due to the Chernobyl NPP accident, 114 IR-non-exposed CLL patients, and 103 sex- and age-matched IR-exposed controls using polymerase chain reaction-restriction fragment-length polymorphism analysis. All investigated polymorphisms were equally distributed between two groups of CLL patients and IR-exposed controls, except that that there was a significant reduction of the common homozygous Lys/Lys XPD genotype among IR-exposed CLL patients (23.7%) compared with IR-exposed controls (45.6%), OR = 0.37; 95% CI = 0.18-0.75; (P = 0.005). The number of IR-non-exposed CLL patients (37.4%) with the Lys/Lys XPD genotype was also decreased compared to IR-exposed controls, although this difference was not significant (P = 0.223). These preliminary data suggest a possible modifying role of Lys751Gln XPD polymorphism for the development of CLL, expecially in radiation-exposed persons.     

Selective pharmacologic inhibition of c-Jun NH2-terminal kinase radiosensitizes thyroid anaplastic cancer cell lines via induction of terminal growth arrest.

CONTEXT: The high radioresistance of anaplastic thyroid cancer (ATC) and cultured ATC cells stipulates for the means of increasing their radiosensitivity. It has been shown that c-Jun NH(2)-terminal kinase (JNK) activation is one of the manifestations of radiation response in ATC cells. OBJECTIVE: Assessment of the effect of selective JNK inhibition on ATC cell radiosensitivity and clarification of the associated mechanisms. RESULTS: The JNK inhibitor markedly suppressed ATC cell growth in a reversible cytostatic manner. The combination treatment with JNK inhibitor plus ionizing radiation induced a significant decrease in clonogenic survival of irradiated cells as compared with either singular treatment. The effect was not due to apoptosis of exposed cells but to a profound senescence-like terminal growth arrest occurring irrespectively of cells' p53 mutational status. Postradiational DNA damage repair was also significantly compromised in the presence of SP600125. CONCLUSIONS: JNK signaling is an essential component of ATC cell proliferation and survival after radiation therapy. Hence, pharmacological interference with JNK pathway in combination with radiotherapy may be a promising treatment of ATC.     

Convergence and divergence in the mechanism of SNARE binding by Sec1/Munc18-like proteins

Sec1Munc18-like (SM) proteins functionally interact with soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) in membrane fusion, but the mechanisms of these interactions differ. In vertebrates, SM proteins that mediate exocytosis (Munc18-1, 18-2, and 18c) bind to the closed conformation of syntaxins 1-4, which requires the N-terminal H(abc) domains and SNARE motifs of these syntaxins. In contrast, SM proteins that mediate Golgi and endoplasmic reticulum fusion (Sly1 and Vps45) bind only to short N-terminal sequences of syntaxins 5, 16, or 18, independently of their H(abc) domains and SNARE motifs. We now show that Munc18-1, Sly1, and Vps45 interact with cognate syntaxins via similar, autonomously folded N-terminal domains, but the syntaxin 5-binding surface of the Sly1 N-terminal domain is opposite to the syntaxin 1-binding surface of the Munc18-1 N-terminal domain. In transfected cells, the N-terminal domain of Sly1 specifically disrupts the structure of the Golgi complex, supporting the notion that the interaction of Sly1 with syntaxin 5 is essential for fusion. These data, together with previous results, suggest that a relatively small N-terminal domain of SM proteins is dedicated to mechanistically distinct interactions with SNAREs, leaving the remaining large parts of SM proteins free to execute their as yet unknown function as effector domains.