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Individual proteins from polo-like kinase (Plk) family fulfil different but critical functions in regulating cell cycle and coordinate cell response to DNA damage. The most studied one from this five member family is Plk1. It is a serine/ threonine kinase that plays a pivotal role in many aspects of mitosis and its deregulation is common in various tumor types where the elevated level is mostly associated with worse prognosis. From the therapeutical point of view, intertwined relationship between Plk1 and p53 protein is very interesting and will be discussed. Not only for these reasons, Plk1 has become an attractive target for antitumor drug development. The most promising seems to be ATP binding site inhibitor Volasertib (BI 6727) which provided a survival benefit for patients with acute myeloid leukemia and is now tested in phase III clinical trial. A new generation of Plk1 inhibitors that target the second druggable domain of Plk1, the polo- box domain, is currently being tested preclinically and are believed to improve Plk1 specificity.

Multiple myeloma is the second most common hematooncological disease characterized by clonal proliferation of plasma cells and monoclonal immunoglobulin production. It is a heterogenous disease; however, dysregulation of cyclins D seems to be an early unifying pathogenic event in multiple myeloma. In almost all patients, there is increased expression level of at least one of the cyclins D. Nevertheless, the mechanism of this increase is unknown in many cases. Next to wellknown roles of cyclins D in the cell cycle, they have many other functions contributing to tumor cell progression. Cyclins D are prognostic markers and are also used for subclassification of multiple myeloma. In this review, we focus on significance of cyclins D in multiple myeloma.

Nijmegen breakage syndrome (NBS) is one of the chromosomal instability syndromes due to DNA repair disorder. The syndrome is autosomal recessive determined, in homozygotes is characterized by many disorders including high predisposition to lymphoreticular malignancy in childhood and adolescence.Laboratory findings represent low level of immunoglobulins, B and T lymphocytes, increased sensitivity to the mutagens, especially hyperradiosensitivity and increased chromosomal instability. Heterozygotes show also elevated radiosensitivity and have an increased cancer risk in adult age. There is no predilection of the malignancy. Colorectal cancer was found often among the relatives of patients with NBS. Majority of the NBS patients are of the Central and Eastern European origin and carry the common founder mutation 657del5 in the NBN gene. The formation of second malignancy both in homozygotes and heterozygotes can be prevented by excluding any radiation. The aim of study is estimation of frequency of 657del5 heterozygotes among patients with colorectal cancer.Within a group of 161 patients with colorectal cancer 5 heterozygotes with 657del5 mutation were registered, e.g. 5-times higher incidence than expected. The elemental prevention in patients with proved positivity of Slavic mutation in NBN gene is to exclude any radiation.

p53 is known as a tumor suppressor gene important for maintenance of genomic integrity. p53 is a short lived protein that is maintained at very low levels in cells. p53 is regulated by Mdm2 protein which participate in p53 rapid degradation. The activation and accumulation of p53 is a response to cellular stress such as DNA damage. Activated p53 is a sequence specific DNA-binding transcription factor and some target genes of its transcriptional activity are important for cell-cycle arrest or for inducing apoptosis. p53 is also used for cancer therapy by p53 gene therapy when p53 is applied into tumors or by reactivation of mutant p53.

Mutations 657del5 and R215W in exon 6 of tumor suppressor gene NBS I are found in 1% Slavic populations. Increased occurrence of cancer was repeatedly reported in adult relatives of patients with Nijmegen breakage syndrome. Among children with oncological problematic, nonsignificantly increased frequency of NBS1 heterozygotes was found, which seems not to play any important role in cancerogenesis in childhood. However, the proportion of NBS heterozygotes among adult patients with malignancies could be significant and their therapy and follow up should respect their hyperradiosensitivity.Mutations in exon were studied in 706 adult patients with malignancies. We found 5 NBS heterozygotes, which not more than the population prevalence (1:129-165). Increased frequency of NBS heterozygotes was found among patients with colon and rectal cancer (2/101), breast cancer (1/60), skin malignancies (1/98).Surprisingly only one NBS heterozygote was found among 228 patients with nonHodgkin lymphoma, the malignancy which is a common complication in NBS homozygotes. Other types of malignancies were uncommon and only one R215W heterozygote was found. Comparison frequency of NBS heterozygotes with incidence NBS among person older than 70 years shows significant difference. Prevention of malignancies by avoidance from ionisation could be realized also in relatives of patients after identification of their genotype.

The autosomal recessive Nijmegen breakage syndrome (NBS) is a DNA repair disorder due to a mutation in the NBS1 gene on 8q21. Hyperradiosensitivity and high risk for lymphoreticular malignancy are important reasons for early diagnosis and prevention by avoidance of ionisation. The frequency of NBS heterozygotes of the mutation 657de15, which is predominant in the Slavic population was estimated to be in the range of 1:90-1:314 in different parts of Poland, and 1:128-154 among Czech newborns, born 20 years ago.Lower prevalence of affected homozygotes born in Czechoslovakia in the period 1969- 1992 (24 among 5.2 million newborns corresponds to 1:271000) than expected on the basis of carrier frequency is explained to be due to underdiagnosing because the rate of prenatal lethality in the NBS families is not increased or it is even lower than in the general population. The underdiagnosing of NBS is emphasized also by the mean age at diagnosis (7.5 years) although severe microcephaly is present at birth. The possibility to offer effective prevention of primary and secondary malignancies becomes the motivation for interdisciplinary collaboration with paediatricians, neurologists, immunologists and clinical geneticists. A decrease of the mean age down to 6 months at diagnosis among the 11 newly recognized patients has been achieved in the previous 4 years. The occurrence of homozygotes was relatively higher in Slovakia with 5 million inhabitants (14 patients in 11 families) than in the Czech Republic with a population of 10 million (21 patients in 14 families), and therefore the frequency of NBS heterozygotes was studied among 2996 newborns born in 2002-2003 in 12 maternity hospitals of west, middle and east Slovakia. Surprisingly, only 3 heterozygotes were found.This discrepancy of heterozygote frequency and the number of homozygotes shows that due to traditional subisolates the population is not in the genetic equilibrium. It explains the high prevalence of alcaptonuria in Slovakia in the middle of last century, which is a rare disorder in other countries.

Cell cycle progression is governed by cyclin dependent kinases (CDK) that are activated by cyclin binding and inhibited by CDK inhibitors. Protein p27Kip1 functions as a CDK inhibitor, which controls the progression from G1 to S phase. Further, p27Kip1 may have a positive regulative influence. In nonneoplastic tissues and in the majority of tumors investigated so far, the immunohistochemical positivity of p27Kip1 showed an inversely proportional relationship to the proliferation index. Among B-cell non-Hodgkin lymphomas, the exceptions to this rule are represented by mantle cell lymphoma, hairy cell leukemia, and the immunoblastic Epstein-Barr virus latent membrane antigen positive diffuse large B-cell lymphoma in AIDS patients. The loss of p27Kip1 expression is a negative prognostic factor in numerous tumors, including the majority of B-cell lymphomas.

Leukemias develop due to defects in proliferation, differentiation and apoptosis, which take place in stem cells or progenitors of hematopoiesis. These processes have several crossing points, one of them is the role of inhibitors of cyclin-dependent kinases. The aim of this study was to study the expression of cyclin-dependent kinases inhibitors p21 Cip and p27 Kip and expression of proliferative antigen Ki-67 in leukocytes of human leukemia.The expression of cyclin-dependent kinases inhibitors was detected at mRNA level mainly by comparative reverse-transcription polymerase chain reaction and in selected samples also by the real-time polymerase chain reaction. While p27 Kip expression in leukocytes of leukemic patients and healthy persons was universal, large differences in expression of p21 Cip were found both among individual patients of the same type of leukemia and between different types of leukemias and healthy persons. The p21 Cip expression was significantly higher in acute leukemias than in chronic ones and healthy persons. A comparison of p21 Cip expression with the clinical outcome of the leukemic patients showed that the group of 14 acute leukemia patients surviving more than 30 months had a significantly lower expression of p21 Cip than 12 patients of this type of leukemia who died within this time limit. Moreover, the results obtained on a smaller set of acute promyelocytic leukemia patients indicated that the lower p21 expression is connected with a better prognosis.Our results pointed out the importance of the cyclin-dependent kinase inhibitor p21 Cip in human leukemias and indicated that the lower p21 Cip expression might be a positive prognostic factor in acute myeloid leukemia patients.