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Ассесорова Ю. Ю.
Республиканский Специализированный Научно-практический Медицинский Центр Гематологии Министерства Здравоохранения Республики Узбекистан
АНОМАЛИИ КАРИОТИПА ПРИ ХРОНИЧЕСКИХ МИЕЛОПРОЛИФЕРАТИВНЫХ
НОВООБРАЗОВАНИЯХ
Резюме. Накопленные к настоящему времени данные о роли генетических событий в патогенезе хронических миелопролиферативных новообразований (ХМПН) позволили разработать новые подходы к диагностике и лечению этих заболеваний. Несмотря на широкое внедрение в медицинскую практику молекулярных методов классическое ци-тогенетическое исследование продолжает занимать одну из основных позиций в диагностике и мониторинге ХМПН. Цитогенетический анализ с использованием технологии дифференциальной окраски хромосом (GTG-бэндинг) позволяет оценивать весь кариотип без привязки к молекулярным локусам и выявлять маркерные, рекуррентные и уникальные хромосомные аномалии, имеющие диагностическое и прогностическое значение. Количественные и структурные аномалии хромосом детектируются в кариотипе лейкозных клонов у значительного количества больных ХМПН, при этом доля пациентов с измененным кариотипом, а также спектр цитогене-тических нарушений нарастают по мере прогрессии заболевания.
В обзорной статье рассматриваются данные литературы, касающиеся основных моментов патогенеза ХМПН и роли широкого профиля клональ-ных цитогенетических аномалий, которые могут быть обнаружены в кариотипе лейкозных клеток больных. На примере маркерной для хронического
миелоидного лейкоза (ХМЛ) транслокации ^9;22) ^34^11.2) рассматривается цитогенетический процесс формирования хромосомных аномалий, а также морфологические различия нормальных и измененных хромосом, позволяющие идентифицировать тип перестройки. С учетом частоты встречаемости в кариотипе лейкозных клеток больных ХМЛ описываются дополнительные цитогенетические аномалии (вторая Р^хромосома, +8, +19, ^17), -7, -У, перестройки с участием хромосомного локуса [3^26.2)] и др.), ассоциирующиеся с переходом заболевания от хронической стадии к стадиям акселерации и бластного криза. Приводится информация о нарушениях кариотипа, выявляемых в дебюте заболевания и при прогрессии истинной полицитемии, первичного миелофиброза, эссенциальной тромбо-цитемии, а также о цитогенетических перестройках, вовлекающих локус гена JAK2, которые могут быть обнаружены при BCR-ABL-отрицательных/JAK2-отрицательных ХМПН. Подчеркивается немаловажность классического анализа кариотипа опухолевых клеток для выявления цитогенетических находок, которые могут определять особенности индивидуального течения заболевания и в дальнейшем войти в перечень маркеров прогностического значения.
Ключевые слова: хронические миелопролифе-ративные новообразования, хромосомные аномалии, стандартное цитогенетическое исследование.
Assesorova Yu. Yu.
Republican Specialized Scientific Practical Medical Center of Hematology of the Ministry of Health of the Republic of Uzbekistan
KARYOTYPE ABNORMALITIES IN CHRONIC MYELOPROLIFERATIVE NEOPLASMS
Abstract. The data accumulated by the present time about the role of genetic events in the pathogenesis of chronic myeloproliferative neoplasms (CMPN) have made it possible to develop new approaches to the diagnosis and treatment of these diseases. Despite the widespread introduction of molecular methods into the medical practice, classical cytogenetic research continues to hold one of the main positions in the diagnosis and monitoring of CMPN. Cytogenetic examination allows to evaluate the entire karyotype without reference to molecular loci and to identify marker, recurrent and unique chromosomal abnormalities having diagnostic and prognostic value. Numerical and structural abnormalities of chromosomes are detected in the karyotype of leukemic clones in a
significant number of patients with CMPN, herewith the proportion of patients with an altered karyotype, as well as the spectrum of cytogenetic disorders increases with the progression of the disease. The review article examines literature data concerning the main points of the pathogenesis of CMPN and the role of a wide profile of clonal cytogenetic anomalies that can be detected in the karyotype of the patient leukemia cells.
Key words: chronic myeloproliferative neoplasms, chromosomal abnormalities, conventional cytogenetic study
Introduction
Chronic myeloproliferative neoplasms (CMPN) are a group of clonal diseases resulting from genetic disorders
in the cells of the myeloid germ of hematopoiesis, which lead to excessive proliferation while preserving the ability of cells to differentiate [1,2]. In accordance with the revision of the "Classification of myeloid neoplasms and acute leukemias" (WHO 2008 2017,), the following nosological forms belong to CMPN: 1) chronic myeloid leukemia (CML), BCR-ABL1+; 2) chronic neutrophilic leukemia (CNL); 3) polycythemia vera (PV) ; 4) primary myelofibrosis (PMF): PMF, prefibrotic/early stage and PMF, obviousfibrousstage; 5) essential thrombocythemia (ET); 6) chronic eosinophilic leukemia, unspecified; 7) myeloproliferative neoplasms (MPN) unclassifiable; 8) mastocytosis [3,4,5,6].
By the present time here is a lot of data on the role of genetic events in the pathogenesis of myeloid neoplasms, which made it possible to develop new approaches to the diagnosis and treatment of these diseases, including targeted therapy drugs. It has been proved that the development of CMPN is based on mutations that alter the work of genes for cell proliferation, differentiation and apoptosis. A changes in the structure and function of these genes leads to the malignant transformation of the precursor cell and the formation of a tumor phenotype, the expansion of malignant cells and the clinical manifestation of cancer. Currently, the genetic characteristics of tumor cells have become a key criterion for the diagnosis and prognosis of CMPN. The diagnostic component allows to verify the diagnosis and specify the type of hemoblastosis. The prognostic component of the genetic characteristics of tumor cells is due to a high degree of correlation between the presence of certain mutations and the clinical features of the disease, including the variant of its course.
Chronic myeloid leukemia
Chronic myeloid leukemia was the first hematological neoplasia in which a specific chromosomal anomaly (Ph-chromosome) was detected, which is a cytogenetic manifestation of translocation t(9;22)(q34;q11.2).
Normally on the long arm of chromosome 9 in the region [9(q34)] there is ABL gene (Abelson gene) with a length of 280 kilobases, which is a proto-oncogene encoding the formation of a protein with a molecular weight of 145 kD. The ABL protein belongs to the family of tyrosine kinases that catalyze the phosphorylation of amino acids. The BCR gene (Breakpoint cluster region) is located on chromosome 22 in the region [22(q11.2)] and has a length of 5.8 kilobases. The expression product of the normal BCR gene is a protein with a molecular weight of 160 kD, which is found in most tissues [7]. In case of t(9;22), DNA breaks at the loci [9(q34)] and [22(q11.2)], with subsequent interchromosomal exchange of terminal fragments 9(q34-ter) and 22(q11.2-ter) and fusion of DNA of the altered chromosomes and of the translocated sequences. The cytogenetic result of this rearrangement are the derivatives of chromosomes 9 and 22. The derivatives and homologous chromosomes that are not changed by the rearrangement have peculiar morphological differences that are clearly recognizable
during karyotyping with usage GTG-binding, but are also distinguishable during routine chromosome staining. Der(9) has a small additional light-colored fragment in the terminal region of the long arm, which makes the altered chromosome 9 visually slightly longer than its normal homologue. In case of high quality of chromosomal preparations and a resolution of more than 400 bands per karyotype, a narrow dark-colored band can also be distinguished on the fragment translocated from the 22nd chromosome to the ninth - the region of its location is identical to the locus [22(q12)]. Der(22), having lost the fragment of the long arm and attaching a much smaller fragment of chromosome 9, acquires a peculiar view of an extremely shortened chromosome called the Philadelphia (Ph) chromosome.
Sometimes in pathogenetic rearrangement with participation of chromosomes 9 and 22 other chromosomes are involved. In such cases, it is customary to talk about variant translocations - t(9;22;V). At variant translocations, the Ph-chromosome may not have the classic form of a shortened derivative 22, since it's lost part is "masked" by an attached fragment of another chromosome, which is equivalent in length. If this fragment is formed mainly by heterochromatin, then the terminal part of the long arm of derivative 22 becomes dark-colored and pathogenetic rearrangement can be detected with GTG-banding. If the "masking" fragment is formed mainly by euchromatin, then it looks light-colored, and participation in the rearrangement of the derivative chromosome 22 cannot be detected by the classical cytogenetic method. However, the presence in the karyotype of derivative 9 with a characteristic morphology, as well as derivatives of other chromosomes involved in variant rearrangement, indicates the presence of pathogenetic rearrangement between chromosomes 9 and 22.
The molecular result of both the classical rearrangement t(9;22)(q34;q11.2) and variant translocations involving chromosomes 9 and 22 is the chimeric oncogene BCR-ABL1, the product of which is a tyrosine kinase with increased activity regulating signals responsible for cell growth, activation of proliferation, differentiation and apoptosis [8,9,10]. Depending on the molecular break point in the BCR gene, the chimeric BCR-ABL1 gene can be represented by variants expressing proteins with different molecular weights. The most common isoforms of the BCR-ABL protein in CML are tyrosine kinases BCR-ABL(p210), expressed in about 95% of patients, BCR-ABL(p190), BCR-ABL(p230) and other, rarer variants (16 variants are known to date) [11,12].
The spectrum of cytogenetic disorders detected during the initial diagnosis of CML may change over time. In addition to marker cytogenetic rearrangement involving chromosomes 9 and 22, other chromosomal mutations may occur in the karyotype of patients, which appear both at the onset of the disease and as it develops [13,14]. In 60-80% of patients with CML,
transformation into a blast crisis is associated with the appearance of secondary chromosomal changes in Ph-positive cells. Most often in the karyotype of leukemic cells, in addition to the Philadelphia chromosome, there is an additional Ph-chromosome, trisomies 8 and 19, isochromosome 17 [15,13]. Secondary chromosomal changes such as chromosome trisomies 6, 10, 12, 14, 17, 21, monosomies of 7, 17, 18, loss of the chromosome Y in men, and rearrangements involving the chromosomal locus [3(q26.2)], for example, such as t(3;21)(q26;q22) or inv(3)(q21q26), detected are less frequently [16,17,18]. The appearance of additional chromosomal abnormalities (ACA) is one of the criteria for the transition of the disease from the chronic phase to the acceleration phase [14] and indicate the rate of blast transformation of the disease, since ACA is associated with a reduction in the duration of remission [19,20]. There are reports of an increase in karyotypic disorders in patients treated with tyrosine kinase inhibitors (TKI), including in Ph-negative cell clone, which, however, save genomic instability [21,22,17,13]. It is known that the appearance of ACA correlates with a high frequency of BCR-ABL1 mutations, that indicates their association with resistance to TKI. Thus, the presence of additional cytogenetic abnormalities is detected in 46% of patients resistant to imatinib [23,24].
Conventional cytogenetic study of the bone marrow (GTG-banding) with an analysis of at least 20 metaphases [3,25] is a mandatory stage of CML diagnosis in accordance with the requirements of the World Health Organization (WHO) and the European LeukemiaNet (ELN, 2020) [4,11]. The need for a conventional cytogenetic study (CCS) in case of suspected CML is due to the fact that this technology makes it possible to analyze the entire karyotype and simultaneously detect any numerical and structural changes in chromosomes within the resolution of the method. The CCS allows to identify not only the translocation t(9;22)(q34;q11.2) and its variants, but also additional chromosomal abnormalities that may be associated with clonal evolution and disease progression [26,27].
In case of uninformativeness of the CCS - due to the insufficient number of dividing cells in the metaphase stage, the unsatisfactory quality of metaphases, which does not allow the identification of chromosomes in accordance with ISCN standards, in the presence of variant translocation, when the Ph-chromosome is masked by fragments of other chromosomes, a molecular cytogenetic study is carried out using the technology fluorescent in situ hybridization (FISH). The use of molecular cytogenetic studies in the diagnosis of CML is also justified in cases where patientsdonot have a classical Philadelphia chromosome in the karyotype, despite the presence of the chimeric gene BCR-ABL1. This situation may be a consequence of cryptic (hidden) insertion of a micro fragment from chromosome 9 to chromosome 22 or the result of two consecutive translocations. In the second case, the classical t(9;22)(q34;q11.2) occurs
with subsequent reverse translocation, which restores the normal morphology of the chromosomes involved, but does not eliminate the molecular disorder due to the preservation of the a micro fragment of chromosome 9 on chromosome 22 [28].
It should be noted that the mandatory studies in the diagnosis of CML also includes a qualitative reverse transcription polymerase chain reaction (RT-PCR) to detect and identify the type of BCR-ABL1 transcript [11]. Quantitative PCR is not a mandatory analysis in the CML diagnosis, however, when monitoring the effectiveness of treatment with TKI, when a complete cytogenetic response has already been obtained, the level of expression of the BCR-ABL gene transcript can only be controlled by a highly sensitive quantitative PCR method, which allows to track of the dynamics of changes in the volume of the tumor clone at the targeted therapy.
Polycythemia vera
Polycythemia vera (PV) is a clonal Ph-negative chronic myeloproliferative disease characterized by proliferation of myeloid hematopoiesis germ with a possible outcome in post-polycythemic myelofibrosis or blast transformation [29].
Activation of the JAK-STAT signaling pathway is considered to be one of the key moments in the pathogenesis of PV [30]. CMPN-related mutations occurring in the JH2 pseudokinase domain of the JAK2 gene lead to constant autophosphorylation and autoactivation of tyrosine kinase (without binding of receptor and ligand), transmission of activating signals to the STAT signaling pathway and cytokine-independent growth of bone marrow cell lines [31]. Almost all patients with PV (95-98%) are carriers of the JAK2(V617F) mutation [32,33,34].
Despite the fact that in most patients with PV, the point mutation JAK2(V617F) is traditionally considered a pathogenetic event, there is a group of patients in whom molecular testing cannot detect this genetic marker. In these cases, the pathogenesis of the disease may be due to a change in the Janus kinase gene by interchromosomal rearrangement. One of the known translocations involving the JAK2 gene located at the chromosomal locus [9p(24.1)], which were identified in BCR-ABL1-negative/jAK2-negative CMPN, is t(1;9) (p36;p24.1). In addition, there are described such genetic changes involving the JAK2 gene locus as t(5;9) (q14.1;p24.1), t(8;9)(q22;p24), t(9;17)(p24;q23), t(4;9)(q25;p24), t(2;9)(p21;p24) and t(8;9)(q13;p24) [35,36,37,38,39,40,41,42].
In general, chromosomal changes are detected in 2033% of patients with PV. At the same time, the proportion of abnormal karyotypes varies from 14-20% among patients in the chronic phase of polycythemia (at the time of initial diagnosis) to 90% among patients in the blast crisis phase. The spectrum of cytogenetic abnormalities in PV, in addition to translocations involving the JAK2 gene locus, may include isolated del(20q), +8 and +9, which are more common in the polycythemic phase;
+1q, more common in post-polycythemic myelofibrosis; complex karyotypes, including -5/del(5q), -7/del(7q), -17/del(17p)/i(17q) and -18, characteristic mainly of acceleration and blast crisis phases [43,44].
Patients with abnormal karyotype have a higher rate of disease progression, a shorter period of transformation into a blast crisis and lower overall survival rates compared to patients with normal karyotype in the same phase of the disease. There are described cases when the other cytogenetic finds were presented in the karyotype of blast cells of patients with PV transformed into acute myeloid leukemia (AML), such as t(3;8) (q26.2;q23) [45], der(18)/t(9;18)(p13;p11), der(9;18) (p10;q10) [46], etc. Evaluation of the prognostic value of individual chromosomal abnormalities, and above all the unique cytogenetic finds, requires more detailed studies. Nevertheless, the significance of the abnormal karyotype as a criterion for risk stratification in PV leaves no doubt.
Primary myelofibrosis
Primary myelofibrosis (PMF) belongs to the number of Ph/BCR-ABL1-negative CMPN and is characterized by clonal proliferation of transformed cells, abnormal expression of cytokines, bone marrow fibrosis, hepatosplenomegaly as a consequence of extramedullary hematopoiesis, symptoms of tumor intoxication, cachexia, leukoerythroblastosis in peripheral blood and leukemic progression [47]. PMF is the least common disease among the group of CMPN, and at the same time has a low survival rate of patients [48].
The key point of the pathogenesis of PMF is the irreversible activation of signaling pathways or individual links in the signal transmission chain that occurs with mutations of certain genes, which leads to stimulation of cell proliferation. The trigger genetic changes in PMF are the JAK2(V617F) point mutation occurring in about 50-60% of cases, mutation W515 in the thrombopoietin receptor (MPL) gene (3-10% of cases) and mutation (ins/del) in the calreticulin (CALR) gene (25-30% of cases) [49,44]. Chromosomal abnormalities are detected in 35-60% of patients with primary myelofibrosis [50,1]. None of the known in PMF cytogenetic changes can not considered a marker, however, such clonal disorders as some deletions (20q-, 13q-), trisomies (+8, +9, +21), as well as complex karyotype disorders can be detected in 1/3 of patients [51,52]. Besides that, another chromosome abnormalities may occur with PMF, such as structural abnormalities of chromosome 1, including 1q duplication, isolated abnormalities of chromosome 7 (-7 or 7q-), chromosome 5 (-5 or 5q-), chromosome 17 - i(17q), inversion of chromosome 3 - inv(3), deletion of the short arm of chromosome 12 (12p-), rearrangements involving chromosome 6, for example, der(6)t(1;6)(q21;p21.3), rearrangements involving the locus [11(q23)] [53,54].
Prolonged proliferation of the tumor clone in PMF leads to the appearance of additional chromosome abnormalities and a higher degree of malignancy, as a result of which a blast crisis develops [55]. Due to
the instability of the genome of malignized cells, in addition to relatively common chromosomal disorders and rearrangements with certain molecular loci, rearrangements with unknown DNA break points may appear during the course of the disease. Loci involved in structural chromosomal disorders can be located both in non-coding regions of the genome, and within the coding or regulatory regions of genes involved in cell division, differentiation, apoptosis, and other processes. Changes in such genetic regions may cause the appearance of more malignant clones of leukemic cells.
A number of studies shows that data on the state of the karyotype of neoplastic cells are an independent prognostic factor of PMF [53,54,47]. As in the case of other types of CMPN, taking into account the effect on the course of the disease and the prognosis, cytogenetic abnormalities encountered in PMF are classified as favorable or unfavorable. The first one includes isolated del(20q) or del(13q). A cytogenetically normal karyotype is also considered prognostically favorable. Unfavorable anomalies associated with the progression and accelerated blast transformation of the disease include all other cytogenetic finds. So, complex karyotypes are usually observed in patients with transformation of PMF into acute leukemia and significantly reduced median survival [56]. Based on the data on cytogenetic abnormalities (isolated or combined disorders +8, 7/7q, i(17q), inv(3), 5/5q, 12p, rearrangements involving the locus [11(q23)], complex karyotype) along with platelet levels and transfusion status N.Gangat et al. (2011) developed a stratification system (Dynamic International Prognostic Scoring System plus, DIPSS+), which allows predicting not only the overall survival of patients with PMF, but also the time to the blast transformation phase [57,58,59].
Essential thrombocythemia
Essential thrombocythemia (ET) is a clonal chronic malignant myeloproliferative disease, characterized by hyperplasia of the megakaryocytic bone marrow germ, persistent thrombocytosis, impaired platelet aggregation ability, the development of intravascular blood clotting and a high risk of vascular complications [60,61,62]. The molecular pathogenesis of ET to a certain extent affects the same mechanisms as in other clonal (Ph)/ (BCR-ABL1)-negative CMPN: the JAK2(V617F) mutation is detected in patients with ET in 23-57% of cases [63]; an MPL mutation (W515L, W515K, Y252H, F126fs) is present in 5% of cases of ET [64,65]; 15.5-32% of cases of ET are due to a mutation of the CALR gene [66,67]. About a third of ET cases are not associated with JAK2, MPL and CALR mutations, but they are caused with changes in other genes (TET2, EZH2, DNMT3A, ASXL1), as well as with epigenetic modifications [68,69,70, 66].
Primary cell clones with cytogenetic abnormalities are quite rare and are detected only in 5-10% of patients with ET [50,1,55]. The spectrum of cytogenetic finds in ET is quite wide. There are reported about cases of ET with trisomy 8, 9, 13, 14, 20 and monosomy
17 [71,72], with rearrangements of chromosome 1, including trp(1)(q21q32) [73,74,75]; with deletions of the long arm of chromosomes 5, 11, 20 [76,72,77,78]; with interchromosomal rearrangements such as t(X;5) (q13;q33) [79], t(13;14)(q32;q32.3) [80], der(1;7) (q10;p10) [81]. Meanwhile, different authors agree that there are no cytogenetic markers of ET of diagnostic value. In ET chromosomal abnormalities occur either as a result of clonal evolution, or as a consequence of cytotoxic drugs exposure. At the same time, the occurrence of cytogenetic rearrangements is usually associated with the development of myelofibrosis and leukemic transformation of the disease. Nevertheless, despite the lack of clarity in understanding the pathogenetic role of chromosomal changes in ET, logging of cases with chromosomal abnormalities can contribute to the detection and identification of genes involved in the pathogenesis of this disease [72].
Conclusion
Despite the widespread use of molecular
technologies, karyotyping still plays a significant role in the research of CMPN. In the diagnosis of CML, conventional cytogenetics is used to identify classical and variant translocations involving chromosomes 9 and 22. The cytogenetic method based on the GTG-binding continues to play a crucial role in the monitoring of CML, allowing to control the dynamics of change of the Ph-positive leukemia clone in the treatment of TKI in the first months of therapy - up to the achievement of a molecular response. The conventional cytogenetic study is the basic method of clonal evolution controlling, since it allows to detect both widespread additional chromosomal anomalies and rearrangements with unknown molecular loci, both single anomalies and complex karyotype changes. In addition, the analysis of the karyotype of tumor cells in CMPN allows to identify cytogenetic finds that can determine the individual course of the disease and in the future may be included in the list of markers of prognostic value.
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