Mature B-CELL neoplasms in Chernobyl clean-up workers of 1986–1987: summary of cytomorphological and immunocytochemical study in 25 years after Chernobyl accident
The data on the verified cases of mature B-cell neoplasms (chronic lymphocytic leukemia – CLL, B-prolymphocytic leukemia, non-Hodgkin’s lymphoma in leukemization phase and multiple myeloma – MM; 146 cases in total) in the consecutive group of Ukrainian clean-up workers within 10–25 years after Chern...
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irk-123456789-323182012-04-17T12:21:36Z Mature B-CELL neoplasms in Chernobyl clean-up workers of 1986–1987: summary of cytomorphological and immunocytochemical study in 25 years after Chernobyl accident Gluzman, D.F. Sklyarenko, L.M. Nadgornaya, V.A. Zavelevich, M.P. Original contributions The data on the verified cases of mature B-cell neoplasms (chronic lymphocytic leukemia – CLL, B-prolymphocytic leukemia, non-Hodgkin’s lymphoma in leukemization phase and multiple myeloma – MM; 146 cases in total) in the consecutive group of Ukrainian clean-up workers within 10–25 years after Chernobyl accident are summarized. B-cell neoplasms represent the most prevalent group among all diagnosed neoplasms of hematopoietic and lymphoid tissues in clean-up worker patients under study (49.4%). MM percentage in the patients of Chernobyl clean-up worker group turned out to be significantly higher than in the patients of the general populations studied at the same period. While the percentage of B-CLL is similar in clean-up worker patients and patients of general population, the trend towards younger age of patients with mature B-cell neoplasms in clean-up worker group is evident. The current concepts on the possible association between mature B-cell neoplasms (mainly B-CLL) and radiation exposure are briefly outlined. Only the precise diagnosis of hematopoietic malignancies combining with large-scale analytical epidemiological studies with careful dose assessment and long-term follow-up may represent the basis for resolving the question whether mature B-cell neoplasms may be radiogenic. 2011 Article Mature B-CELL neoplasms in Chernobyl clean-up workers of 1986–1987: summary of cytomorphological and immunocytochemical study in 25 years after Chernobyl accident / D.F. Gluzman, L.M. Sklyarenko, V.A. Nadgornaya, M.P. Zavelevich // Experimental Oncology. — 2011. — Т. 33, № 1. — С. 47–51. — Біліогр.: 32 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/32318 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions |
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Original contributions Original contributions Gluzman, D.F. Sklyarenko, L.M. Nadgornaya, V.A. Zavelevich, M.P. Mature B-CELL neoplasms in Chernobyl clean-up workers of 1986–1987: summary of cytomorphological and immunocytochemical study in 25 years after Chernobyl accident Experimental Oncology |
| description |
The data on the verified cases of mature B-cell neoplasms (chronic lymphocytic leukemia – CLL, B-prolymphocytic leukemia, non-Hodgkin’s lymphoma in leukemization phase and multiple myeloma – MM; 146 cases in total) in the consecutive group of Ukrainian clean-up workers within 10–25 years after Chernobyl accident are summarized. B-cell neoplasms represent the most prevalent group among all diagnosed neoplasms of hematopoietic and lymphoid tissues in clean-up worker patients under study (49.4%). MM percentage in the patients of Chernobyl clean-up worker group turned out to be significantly higher than in the patients of the general populations studied at the same period. While the percentage of B-CLL is similar in clean-up worker patients and patients of general population, the trend towards younger age of patients with mature B-cell neoplasms in clean-up worker group is evident. The current concepts on the possible association between mature B-cell neoplasms (mainly B-CLL) and radiation exposure are briefly outlined. Only the precise diagnosis of hematopoietic malignancies combining with large-scale analytical epidemiological studies with careful dose assessment and long-term follow-up may represent the basis for resolving the question whether mature B-cell neoplasms may be radiogenic. |
| format |
Article |
| author |
Gluzman, D.F. Sklyarenko, L.M. Nadgornaya, V.A. Zavelevich, M.P. |
| author_facet |
Gluzman, D.F. Sklyarenko, L.M. Nadgornaya, V.A. Zavelevich, M.P. |
| author_sort |
Gluzman, D.F. |
| title |
Mature B-CELL neoplasms in Chernobyl clean-up workers of 1986–1987: summary of cytomorphological and immunocytochemical study in 25 years after Chernobyl accident |
| title_short |
Mature B-CELL neoplasms in Chernobyl clean-up workers of 1986–1987: summary of cytomorphological and immunocytochemical study in 25 years after Chernobyl accident |
| title_full |
Mature B-CELL neoplasms in Chernobyl clean-up workers of 1986–1987: summary of cytomorphological and immunocytochemical study in 25 years after Chernobyl accident |
| title_fullStr |
Mature B-CELL neoplasms in Chernobyl clean-up workers of 1986–1987: summary of cytomorphological and immunocytochemical study in 25 years after Chernobyl accident |
| title_full_unstemmed |
Mature B-CELL neoplasms in Chernobyl clean-up workers of 1986–1987: summary of cytomorphological and immunocytochemical study in 25 years after Chernobyl accident |
| title_sort |
mature b-cell neoplasms in chernobyl clean-up workers of 1986–1987: summary of cytomorphological and immunocytochemical study in 25 years after chernobyl accident |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2011 |
| topic_facet |
Original contributions |
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http://dspace.nbuv.gov.ua/handle/123456789/32318 |
| citation_txt |
Mature B-CELL neoplasms in Chernobyl clean-up workers of 1986–1987: summary of cytomorphological and immunocytochemical study in 25 years after Chernobyl accident / D.F. Gluzman, L.M. Sklyarenko, V.A. Nadgornaya, M.P. Zavelevich // Experimental Oncology. — 2011. — Т. 33, № 1. — С. 47–51. — Біліогр.: 32 назв. — англ. |
| series |
Experimental Oncology |
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47 Experimental Oncology 33, 47–51, 2011 (March)
MATURE B-CELL NEOPLASMS IN CHERNOBYL
CLEAN-UP WORKERS OF 1986–1987: SUMMARY
OF CYTOMORPHOLOGICAL AND IMMUNOCYTOCHEMICAL STUDY
IN 25 YEARS AFTER CHERNOBYL ACCIDENT
D.F. Gluzman*, L.M. Sklyarenko, V.A. Nadgornaya, M.P. Zavelevich
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv, Ukraine
The data on the verified cases of mature B-cell neoplasms (chronic lymphocytic leukemia – CLL, B-prolymphocytic leukemia, non-
Hodgkin’s lymphoma in leukemization phase and multiple myeloma – MM; 146 cases in total) in the consecutive group of Ukrainian
clean-up workers within 10–25 years after Chernobyl accident are summarized. B-cell neoplasms represent the most prevalent group
among all diagnosed neoplasms of hematopoietic and lymphoid tissues in clean-up worker patients under study (49.4%). MM percentage
in the patients of Chernobyl clean-up worker group turned out to be significantly higher than in the patients of the general populations
studied at the same period. While the percentage of B-CLL is similar in clean-up worker patients and patients of general population,
the trend towards younger age of patients with mature B-cell neoplasms in clean-up worker group is evident. The current concepts
on the possible association between mature B-cell neoplasms (mainly B-CLL) and radiation exposure are briefly outlined. Only the
precise diagnosis of hematopoietic malignancies combining with large-scale analytical epidemiological studies with careful dose assess-
ment and long-term follow-up may represent the basis for resolving the question whether mature B-cell neoplasms may be radiogenic.
Key Words: Chernobyl, clean-up workers, leukemia, mature B-cell neoplasms.
Chernobyl accident remains the worst in history
of nuclear industry. Oncohematological consequences
have been still very controversial, even in 25 years
since the disaster.
The most intricate in this respect is the problem
of the putative association between chronic lympho-
cytic leukemia (CLL) as well as other mature B-cell
neoplasms and radiation exposure. CLL (and mature
B-cell neoplasms in total) is one of the most prevalent
forms of the tumors of hematopoietic and lymphoid
tissues in the population of Europe and North America.
Chernobyl accident has resulted in the radiation expo-
sure of the numerous group of population within the dif-
ferent dose range. Clean-up workers of 1986–1987 with
the average dose estimate of approximately 100 mGy
represent the most suffered group [1, 2].
Despite several research projects in Ukraine, Rus-
sian Federation and Belarus, the question whether the
incidence of CLL among the exposed clean-up work-
ers has been still a point of controversy. The lack
of database of verified diagnoses in most research
presented within 25 years after Chernobyl accident
is still a problem preventing from accurate analysis
of the data by various epidemiological approaches.
The aim of the study is to summarize the data on the
verified cases of mature B-cell neoplasms (CLL, B-
prolymphocytic leukemia, non-Hodgkin’s lymphoma
in leukemization phase and multiple myeloma) in the
consecutive group of Ukrainian clean-up workers
within 10–25 years after Chernobyl accident diag-
nosed in the Reference Laboratory representing the
public service in RE Kavetsky Institute. The hemato-
poietic malignancies were diagnosed based on cyto-
morphology, cytochemistry and immunophenotyping
in accordance with FAB, WHO, EGIL, ICD-10 and ICD-
O-2 classifications.
Several aspects pertaining to the up-to-date views
on the association between CLL and radiation expo-
sure are also briefly outlined.
The research has been carried out within the
framework of the collaboration with French-Ukrainian
Center “Children of Chernobyl” set up in 1991 and
Japanese-Ukrainian Leukemia/Lymphoma Study
Group set up in 1998.
PATIENTS AND METHODS
In all, 403 clean-up workers from Kyiv city and
majority of the regional hospitals of Ukraine with sus-
pected oncohematological disorders were examined.
All the clean-up workers referred to the Reference
Laboratory in 1996–2010 were examined consecutively
without any previous selection of the cases. The radia-
tion dose load of the clean-up workers under study
varied from 75 to 250 mGy. The consecutive patients
of general population aged over 30 (the total number
of patients — 2697), mainly the residents of Kyiv city
and district (hereinafter referred as “general popula-
tion”), diagnosed in the Reference Laboratory at the
same period comprised the group of comparison.
Bone marrow and peripheral blood smears stained
by May-Grunwald-Giemsa were studied morphologi-
cally. Activities of myeloperoxidase, acid phosphatase
(tartrate-sensitive and tartrate-resistant), non-specific
esterase (sodium fluoride-sensitive), naphtol-AS-D-
chloracetate esterase, alkaline phosphatase were
analyzed cytochemically. Glycogen was assayed
cytochemically by PAS-reaction. Immunocytochemi-
Received: February 25, 2011.
*Correspondence: Fax: +380 44 258 1656
E-mail: vals@onconet.kiev.ua
Abbreviations used: ATM – ataxia teleangiectasia; CLL – chronic
lymphocytic leukemia; MM – multiple myeloma; NHL – non-
-Hodgkin’s lymphoma.
Exp Oncol 2011
33, 1, 47–51
48 Experimental Oncology 33, 47–51, 2011 (March)
cal techniques (APAAP, LSAB-AP) and a broad panel
of monoclonal antibodies (MoAbs) against lineage
specific, differentiation and activation antigens of leu-
kocytes were employed for immunophenotyping patho-
logical cells in blood and bone marrow [3]. The main
forms and cytological variants of hematological malig-
nancies were diagnosed according to FAB-classifica-
tion and REAL classification schemes. In 2001–2010 the
diagnostic findings were revised in accordance with
recently published new WHO classification [4].
RESULTS
In 118 of 403 patients in clean-up worker group, the di-
agnosis of tumors of hematopoietic and lymphoid tissues
has not been confirmed. In 285 Chernobyl clean-up work-
ers various forms of malignant diseases of hematopoietic
and lymphoid tissues were registered (see Table).
Table. Summary of tumors of hematopoietic and lymphoid tissues diag-
nosed in Chernobyl clean-up workers (1996–2010)
Disease Number of cases
and percentage
Mature B-cell neoplasms
Chronic lymphocytic leukemia 77 (26.10 %)
B-cell prolymphocytic leukemia 4 (1.36 %)
Hairy cell leukemia 11 (3.73 %)
Non-Hodgkin’s lymphoma in leukemization phase 35 (11.79 %)
Multiple myeloma 19 (6.44 %)
Mature T-cell neoplasms
T-cell prolymphocytic leukemia 2 (0.68 %)
T-cell large granular lymphocytic leukemia 5 (1.69 %)
Sezary syndrome 3 (1.02 %)
Myeloproliferative neoplasms
Chronic myelogenous leukemia 27 (9.01 %)
Polycythemia vera 6 (2.03 %)
Primary myelofibrosis 4 (1.36 %)
Essential thrombocythemia 10 (3.39 %)
Chronic eosinophIlic leukemia / eosinophilic syndrome 3 (1.02 %)
Myelodysplastic / myeloproliferative neoplasms
Chronic myelomonocytic leukemia 10 (3.39 %)
Myelodysplastic syndromes 16 (5.42 %)
Acute leukemias
Acute myeloid leukemia 46 (15.60 %)
Acute lymphoblastic leukemia 17 (5.76 %)
The mature B-cell neoplasms constitute in total
about half of all cases of tumors of hematopoietic and
lymphoid tissues in our group of clean-up workers,
namely 49.42%, with B-CLL being predominant form
of mature B-cell neoplasms (26.10%).
Immunophenotype of all B-CLL cases under study
was quite typical (HLA-DR+, CD19+, CD20+, CD22low,
CD5+, CD23+, CD79a+, CD10–, sIglow).
B-cell prolymphocytic leukemia (B-PLL) was regis-
tered in 4 patients of clean-up worker group (1.36%)
and 23 patients of general population group (0.85%).
The phenotype of hairy cell leukemia (HCL) was
(HLA-DR+, CD19+, CD20+, CD22+, CD5–, CD23–, CD10–,
CD25+, sIgbright , κ+λ+) with relative frequency of 3.73%
in clean-up workers and 4.73% in general population.
Different types of B-cell non-Hodgkin’s lym-
phoma (NHL) in leukemization phase were diagnosed
in 35 (11.79%) patients of Chernobyl clean-up worker
group with 10.97% cases in general population. Tak-
ing into account the new WHO classification, follicular
lymphoma was verified in 11 patients (CD19+, CD20+,
CD22+, CD79a+, CD10+, CD5–, CD43–), lymphoplas-
macytic lymphoma — in 7 patients (CD19+, CD20+,
CD22+, CD79a+, CD38+, CD5–, CD10–, CD23–), mantle
cell lymphoma — in 3 patients (HLA-DR+, CD19+, CD20+,
CD22+, CD5+, cyclin D+, CD23–, CD10–). Splenic margin-
al zone B-cell lymphoma characterized in some cases
by the abundance of villous lymphocytes exhibiting high
tartrate-sensitive acid phosphatase activity (HLA-DR+,
sIgbright, CD19+, CD20+, CD22+, CD5–, CD23–, CD10–,
CD43–) was revealed in 5 patients. Diffuse large B-cell
lymphoma (CD19+ CD20+ CD22+ CD79a+ CD5– CD22–)
was revealed in 6 patients and extranodal marginal zone
B-cell lymphoma of MALT type (CD19+ CD20+ CD22+
CD79a+ CD23–CD5– CD10–CD43+/–) — in 3 patients.
Multiple myeloma (MM) was diagnosed in 19 pa-
tients of clean-up worker group (6.44%). In 7 patients,
the disease developed at the age below 50. Accord-
ing to the data of the available literature, the main
peak of MM incidence could be registered at the age
of 70–80. In our study, MM percentage in the pa-
tients of Chernobyl clean-up worker group turned out
to be significantly higher than in the patients of the gen-
eral populations studied at the same period (4.00%).
DISCUSSION
The data provided above seem to represent one
of the attempts to characterize in details the major
forms and cytological variants of mature B-cell neo-
plasms in Chernobyl clean-up workers that became
evident in 10–25 years after their exposure to radia-
tion. The comparison of the relative distribution of the
specified forms of mature B-cell neoplasms in the
patients diagnosed among Chernobyl clean-up work-
ers demonstrates the increasing multiple myeloma
rate while no differences in the percentage of NHL
(in leukemization phase) and B-CLL between clean-
up workers and general population.
A study of a cohort of 71,870 Russian-resident
males who were engaged in recovery operations within
30-km zone in 1986–1990 revealed a total of 58 mor-
phologically verified leukemia cases diagnosed in this
cohort between 1986 and 1998, of which 16 cases
(27.6%) were CLL [5]. In multinational case-control
study in group of clean-up workers (1986–1987) from
Belarus, Russia and Baltic countries, 32 (27.4%) cases
of CLL and 34 (29.0%) cases of NHL were recorded
[6]. In Ukrainian-American nested case-control study
of leukemia and related disorders based on a cohort
of 110,645 clean-up workers (1986–1990), the follow-
up (until 2000) has yielded 101 leukemia cases with
49 (48.9%) CLL and 8 (7.93%) MM [7].
According to the data of the scientists from the
Research Center for Radiation Medicine of the Na-
tional Academy of Medical Sciences of Ukraine, CLL
in Chernobyl clean-up workers develops at younger
age with more advanced symptoms and more aggres-
sive course and resistance to standard therapy [8].
The absence of demonstrable association between
CLL in Japanese A-bomb survivors (partly due to the
rarity of CLL among Japanese in general) and the results
of earlier epidemiological studies in patients treated with
radiation [9, 10] have led to the long persisted conclu-
sion that CLL is not associated with radiation exposure
49 Experimental Oncology 33, 47–51, 2011 (March)
[11, 12]. Nevertheless, recently these assumptions
have been challenged. The epidemiological data based
on studies in occupationally and medically exposed
populations have required revising several aspects
pertaining to CLL radiogenicity [11–15].
The clinical characteristics of CLL including its long
latency and asymptomatic period, higher prevalence
at older age, mild symptoms, and low rate of fatal
outcomes resulted in underestimation of CLL judging
by death certificates entries [13]. Many patients diag-
nosed with CLL often live for many years not requiring
hospitalization and die from cases unrelated to their
CLL (infectious or malignant diseases).
Although CLL as the clinical and hematological
entity is recognized for more than hundred years, only
in the middle of 70-s of the last century this entity was
introduced into International Classification of Diseases
(ICD-8) [12] allowing for separate accounting for CLL
and ALL incidence (in Ukraine such amendments came
into force only in 1989).
In research of the recent decade, new data on the
origin and differentiation of B lymphocytes, the biol-
ogy of leukemic lymphocytes, and peculiar clinical
features of B-CLL have been obtained. The specific
immunophenotypic and molecular genetic features
of B-CLL have become evident. As a result, the novel
hypotheses on the origin and the evolution of this dis-
ease have been put forward. In parallel, the methods
for the laboratory diagnosis have been improved.
Earlier, CLL in majority of cases was considered
to originate from naïve CD5+CD23+IgM+IgD+ B cells
capable of recirculation and in some cases from CD5+
IgM+ subpopulation of memory B cells with mutation
of IgHV genes. The results of the recent studies dem-
onstrate that in CLL the initial genetic impairments
occur in immature B cells of bone marrow. The sub-
sequent repetitive antigenic stimulation with additional
genetic lesions results in neoplastic transformation
and leukemia development [16, 17]. Alternatively, the
initiating events in CLL could occur in immature B cells
circulating in peripheral blood, and in case of small
lymphocytic lymphoma (SLL) — in similar B cells resid-
ing upon homing in lymph nodes or spleen.
One of the central points in pathogenesis of CLL
is B cell receptor involved in transduction of signals
associated with CLL cell microenvironment. The direct
contact between B cells and accessory and stromal
cells is also of high importance.
CLL is known to exhibit stronger familial tendency
than any other malignancy. CLL risk is 3-6-fold in-
creased in the relatives of CLL patients [12]. The role
of hereditary factors in CLL is supported by the fact
of strikingly low CLL incidence in China, Japan and
Philippines. Such low CLL rates in Asians appear
to be stable despite the migration of native popula-
tion to western countries [17]. Adverse environmental
exposure including the infectious agents, antigens,
genotoxic chemicals and ionizing radiation may also
contribute substantially to CLL development [12].
Prior to REAL classification (1994) and WHO clas-
sification of tumors of hematopoietic and lymphoid
tissues (2004, 2008), the strict criteria for differ-
entiating between B-CLL and other mature B cell
neoplasms (B-cell prolymphocytic leukemia, hairy
cell leukemia as well as nodular marginal zone lym-
phoma, follicular lymphoma and mantle cell lymphoma
in leukemization phase) were lacking. Likewise, it was
not possible to differentiate between B-CLL and rare
T cell prolymphocytic leukemia, T-cell large granular
lymphocytic leukemia, chronic lymphoproliferative
disorder of NK cells. In this respect, monoclonal B-
cell lymphocytosis (MBL) as the condition that may
precede CLL deserves close attention [18]. In MBL,
immunophenotype and the chromosomal abnor-
malities are similar to those of CLL. MBL is detected
up to 5% of adult population depending on their age
distribution. In this connection, the assay of pheno-
typic subpopulations of lymphocytes by flow cytometry
seems to be of high importance in periodical laboratory
examination of blood in clean-up workers.
We suppose that the integration of CLL and SLL into
one nosological group referred to as CLL/SLL seems
rather unwarranted since the term SLL is used mainly
by hematopathologists for non-leukemic cases with
histopathology and immunophenotype correspond-
ing to that of CLL. This question may complicate the
epidemiological studies involving such entity.
For many years, CLL cases have been underes-
timated. Even as late as in 1975, for diagnosing CLL
lymphocyte count over 15 x 109/L was required. There-
fore, many low count cases have gone unrecognized.
At present, the diagnostic criteria for CLL is formulated
as ≥ 5 x 109/L monoclonal lymphocytes with CLL phe-
notype in peripheral blood.
In 70–80s of the last century, the first reports de-
scribing specific chromosomal translocations in CLL
begin to appear. At present, the broad spectrum
of cytogenetic and molecular biological alterations
are known to be associated with CLL development.
The heterogeneity of the clinical manifestations
in CLL depends largely on the differences in the muta-
tional status of variable regions of the genes of heavy
chains of immunoglobulins (IgHV). Somatic mutations
of IgHV genes are detected in more than 50–60% of CLL
cases [16, 17]. The absence of the somatic mutations
and presence of CD38 and ZAP-70 expression appear
to be associated with more unfavorable course of the
disease. Mutations in several other genes such as BCL6,
MYC, PAX5 and RHOH also modify the course of the dis-
ease in the patients with non-mutated immunoglobulin
genes. In the stable course of the disease in patients
with somatic mutations of IgHV genes, overexpression
of WNT3, CTLA4, ADAM29, TCF7 is evident [17].
Some of the somatic mutations in CLL may
be a consequence of the environmental exposures
[11]. The clonal chromosomal aberrations are revealed
in 50–80% of CLL cases [16, 17]. About half of CLL pa-
tients with clonal chromosomal abnormalities are the
carriers of one abnormality while there are at least two
50 Experimental Oncology 33, 47–51, 2011 (March)
genetic abnormalities in another half of the patients.
The use of FISH technique allows for clarifying the
frequencies of the most prevalent chromosomal aber-
rations in CLL. The most common are 13q14 deletion,
trisomy 12 and 11q22-q23 deletion while 6q21 and
7p13 deletions are less prevalent [12, 13]. It is impor-
tant that the most common 13q14 deletion involves
the region covering two micro RNA genes, mir15 and
mir16 [19]. These micro RNA may be important for
regulating the functions of genes which may have rel-
evance to cancer in general and CLL in particular [20].
The above mentioned micro RNA genes have been
shown to be deleted or down-regulated in most cases
of CLL [21]. It seems that this deletion confers a selec-
tive advantage possibly predisposing B-cell clones
to undergo additional mutations via regulatory path-
ways involving key oncogenes [22]. Since mir15 and
mir16 normally interact with BCL6, their absence in CLL
may be important for preventing apoptosis.
In some CLL patients, trisomy 12 may be detected
in 25–72% of malignant cells [16, 17]. At present, the
genes of chromosome 12 that may facilitate leukemic
transformation upon increase in copy number have
not been identified. The cases of CLL with the partial
trisomy 12 limited by the long arm seem to be useful
clue in identifying such genes since this chromosomal
region contains several genes coding for growth fac-
tors which may well be the putative genes involved
in the development of CLL [16, 17]. It is also of high
importance that 12q22 region contains CLLH1 gene
that is the first gene recognized as CLL-specific.
11q22-q23 deletion is a characteristic feature
of peculiar CLL variant [23, 24]. The detailed map-
ping of 11q22.3-q23.1 region revealed the minimal
deletion area containing NPAT, CUL5, PPP2RIB, DDXP
genes known to be involved in controlling cell cycle
and apoptosis. The same region contains ATM gene
considered as caretaker of genome and playing a role
in DNA-damage recognition and signaling. ATM gene
is responsible for inherited autosomal recessive dis-
order ataxia teleangiectasia considered as a marker
for cancer predisposition [25] with neoplasms of the
lymphoid system being predominant [26]. When ATM
mutation affects both ATM alleles, a risk of leukemia
is approximately 70 times higher than in general
population [27]. The presence of somatic mutations
of ATM gene in the cells of CLL patients suggests their
possible role in CLL pathogenesis.
The first report of ATM involvement in sporadic B-
CLL was published in 1999 [28]. Several other studies
reported similar evidence for ATM role in CLL [29, 30].
50% of ATM mutations affect phosphatidylinositol 3-ki-
nase domain of ATM protein which is highly conserved
among ATM-related proteins and crucial for protein
kinase activity of ATM [25].
Sometimes, 17p13 deletion is detected in leukemic
cells of CLL patients. This is the region wherein p53 gene
is localized. The role of p53 for apoptosis induction
in cells in response to their damage is well known. In this
context, it is important that 10–20% cases of CLL with
resistance to therapy and unfavorable prognosis dem-
onstrate the abnormalities of p53 [23, 24].
6q deletion in CLL is considered as secondary one
being associated with other chromosomal aberrations.
Recently, the epigenetic alterations including DNA
methylation patterns have been also considered in the
pathogenesis of CLL [31, 32].
To sum up, the current understanding of the patho-
genesis of CLL has challenged the previous views
on the absence of association between mature B-cell
neoplasms and radiation exposure. Only the precise
diagnosis of hematopoietic malignancies combining
with large-scale epidemiological studies with careful
dose assessment and long-term follow up may repre-
sent the basis for resolving the question whether CLL
may be radiogenic as well.
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