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Chromosome number abnormalities in Iranian patients with acute lymphoblastic leukemia and myeloid leukemia

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  • Save Clinical M edicine and Diagnostics 2012, 2(5): 45-50 DOI: 10.5923/j.cmd.20120205.01 Numerical Chromosomal Abnormalities in Patients with Acute Lymphoblastic and Myeloid Leukemia in Iran Ali mohamad malekasgar1,*, Mohamad Pedram2, Sayyed kamal Eshagh housaini3 1Dept. of basic science, genetic unit, qom university of medical sciences, Iran 2thalassmia and hemoglobinophaties research center, Ahvaz-Iran Ahwaz Jondishapur University of M edical Sciences, Iran 3Dept. of oncology, Qom university of medical sciences, Iran Abstract The majority of cases of ALL demonstrate an abnormal karyotype, either in chro mosome nu mber or structural changes. Abnormal chro mosome number in childhood acute lymphoblastic leukemia defines distinct biological subgroups with a different response to treatment. The tubes are cultured with three different protocols to save time if one protocol failed. Cultures are then harvested, and cells are fixed and chromosome spreads are prepared. Of 25 patient studied, one patient had psudodiploid karyotype, three patients had tetra-ploid karyotype, four patients had low hypo-diploid karyotype, four patients had high hyper-diploid karyotype, five patients had low hyper-d iploid karyotype and eight patients had normal karyotype. Some other factors like, Age, Sex, Consanguinity, Hemoglob in, W BC count, and Type of the leukemia cell also have been evaluated. We found excess number of patients having hypodiploid karyotype but still response to treatment protocols were satisfactory. By co mparison between 4 different cultures methods, we find d irect method to be more efficient for ploidy an aly s is . Keywords A LL, AML, Karyotype, Plo idy, Leukemia 1. Introduction Acute lymphoblastic leukemia (A LL) is characterized by clonal pro liferation, accumu lation, and tissue infiltrat ion of neoplastic cells. They are main ly regarded as childhood diseases, with an early incidence peak at two to five years of age, where they represent about 80% o f the childhood leukemia in the United States, and occur with an incidence of 30 cases per one million population per year[1]. A basic princip le of the WHO classification is that the diagnosis of myelo id and lymphoid malignancies should be based on the integration of the information derived fro m genetic, immunophenotypic, biological, and clinical features in order to better define specific disease entities. In fact, genetic findings may predict the prognosis and biologic properties of the leukemia more consistently than does morphology[2]. Chro mosomal abnormalities in childhood ALL had important significance related to prognosis, diagnosis and management. Chro mosomal classification in ALL is based on the number of chro mosomes in abnormal cells (p loidy pattern) as well as the structural changes. Abnormal ch ro moso me n u mbers in ch ildhood acute ly mp h o b last ic leu kemia, d efin es d is t in ct b io lo g ical * Corresponding author: (Ali mohamad malekasgar) Published online at Copyright © 2012 Scientific & Academic Publishing. All Rights Reserved subgroups with a different response to treatment[3,4]. The largest subgroup within the non-T cells A LL (appro ximately 25%) is the hyper-diploid group, which is associated with favorable characteristics and outcome[3,4,5]. In contrast the hypo-diploid and near-haploid ALL is much rarer (1%) and has shown a very poor outcome with the few intensive protocols reported[6,7]. Near haplo id has been reported in around 41 children[5,8,9] and in six addit ional children within a clinica l study[9]. The majority of cases of ALL demonstrate an abnormal karyotype either in chro mosome nu mber or as structural changes such as trans-locations, inversions, deletions, etc. These changes were detected in only half of A LL patients in the first banding studies[10]. The scantiness of information gained fro m chro mosomal findings in ALL has been in large part, due to technical difficult ies. The emerg ing theory for the role of constitutional trisomy 21 in leu kaemia predisposition is that genes on this chromosome contribute to the expansion of haematopoetic co mpart ments during early development that result in an increased pool of potential tumour precursor cells[11]. Chro mosome studies in ALL exh ibit poor morphology. Chro mosomes tend to spread poorly, and appear blurred and fuzzy with indistinct marg ins, making banding studies challenging or even impossible[12,13] Improvements in spreading and banding techniques have resulted in higher rates of detection, and most studies now report chromosomal changes in 60% to 85% of A LL cases.[14,15]. We have conducted this study to evaluate numerical 46 Ali mohamad malekas gar et al.: Numerical Chromosomal Abnormalities in Patients With Acute Lymphoblastic and Myeloid Leukemia in Iran abnormalities in these patients for better management of patients admitted to this hospital by using different cell culture and chemotherapy treatment protocols. 2. Material and Methods three fore-mentioned methods. Quality of spreads in these methods were compared. Good and analysable spreads could obtain with direct method for plo idy determination in most cases, but for structural chromosomal analysis, flurodeo xy uridine (FudR) method proved to be satisfactory. This work was conducted on 25 cases (five cases with AML and 19 cases with A LL) referred to our laboratory for karyotype and ploidy determination of chro mosomes after getting a written consent from their parents. Only new diagnosed cases (from December 2007 to July 2008) were included in this survey and old cases which have been already started chemotherapy treatment were excluded. 0.5-1 ml of bone marrow aspirate were collected in centrifuges tube containing five ml RPMI co mplete with 1% preservative-free heparin . In few cases where the bone marrow samples were unavailable or failed to grow in culture, blood samp les were used. The optimu m cell density for a bone marrow cu lture is 106 cell/ ml. All samples were optimized for cell density, using hemocytometer (slide counter chamber). In most cases, the preferred culture method was overnight colcemid (ONC), fo llo wed by flurodeo xy uridine (FudR) and 24 hour protocols. In AML samples the preferred technique was FUdR, followed by 24 hours cultures and then ONC. For each patient we set up at least three cu lture tubes including one d irect cu ltures method[12] and two out of the 3. Results 3.1. Number of Patient, Age, Sex, Ethnic Groups, Consanguinity, Hemoglobi n Rate and WBC Count Factors Bone marrow (19 patient) o r b lood (six patients) samples fro m 25 patients, suffering fro m leukemia referred fro m Shafa hospital have been analy zed. A mong 25 patients participated, 19 A LL (including two cases with T-ALL and seven cases with B-ALL), five AM L and one unidentified case was present. Out of 25 patients, 16 males (64%) and nine females (36%) are recorded. The age of patients ranges fro m 1.5 to 12 with med ian age of 5.82 years. Of 25 parents participated, eight couples (32%) have not reported the type of their marriage, (consanguinity) and out of remaining 17 (68%) couple, 11 couples (44%) had consanguineous marriage (10 firsts and one second) and six couples (24%) had non-consanguineous marriage. Table 1 Table 1. P at ient s paramet ers and chromosomal ploidy groups Patient No. 1 2 3 4 5 6 7 8 9 10 11 Ploidy groups Leukemia subtype HB/g WBC/μ dl l T reatment result High hyper diploid low hyper diploid Low Hypo diploid Near tetraploid. 46,Ring Ch. Low Hyper diploid Normal AML M5 B-ALL L1 5.5 1900 7.7 7500 AML-M4 7.9 6300 BALL L1 T-ALL L2 7.7 3400 10.7 10400 6.9 20000 Remission Remission No Remission Remission Remission Remission Normal B-ALL -L2 13.5 4200 Remission Normal B-ALL 5 –L1 Low Hyper diploid (Down) B-ALL -L2 High hyper diploid AML-M1 6 & Near triploid 5700 Remission 2500 Remission 90000 Remission Pseudo diploid B-ALL -L2 5.1 7400 Remission Type of cell involved Myeloid B cell Myeloid B cell T cell B cell B cell B cell Myeloid B cell Primary diagnosis Consan Sex Ethnic Age guinity Aplastic First 1.5 anemia Male Arab cousin Non 6 anemia Female lur conan. First 5.5 AML Female lur cousin Unkno 6.5 Pansitopny Male lur wn First 3.5 Pansitopny Male Arab cousin Burkit Unkno 11 lymphoma Male wn lur First 3 Pansitopny Female fars cousin Non 3 ALL Female Arab cona. Non 5 ALL Male lur cona. AML Unkno 11 Female Arab wn First Anemia Male Arab 9 cousin. Clinical M edicine and Diagnostics 2012, 2(5): 45-50 47 Hyper diploid & 12 B-ALL -L2 10 9900 Remission B cell near tetraploid Unkno 2 ALL Male Arab wn Normal Non 5 13 T-ALL -L2 11.4 273000 Remission T cell anemia Male lur cona. Normal Unkno 4 14 B-ALL -L2 5.9 6100 Remission B cell ALL Male Arab wn Low Hypo Unkno 1 15 B-ALL -L2 7.3 33500 Remission T cell AML Male lur diploid wn Low Hyper 16 diploid & Near B-ALL -L2 5.4 1200 Remission B cell triploid Unkno 7 ALL Female lur wn near tetraploid & 17 B-ALL -L2 7.4 26800 Remission B cell Hyper diploid First 2 ALL Female lur cousin. Low Hypo No 18 diploid AML- M3 8.7 8600 Remission Near haploid AML Unkno 12 Male Arab wn Low hyper 19 B-ALL -L1 7.6 8600 Remission B cell diploid Second 4.5 ALL Female Fars cousin Normal B-ALL First 8 20 5.9 2300 Remission B cell Leukemia Male Arab –L1 cousin. Low hyper B-ALL First 2 21 7.8 2000 Remission B cell Leukemia Male Arab diploid –L1 cousin. Normal Non 9 22 B-ALL -L2 6.1 83900 Remission B cell Leukemia Male Arab cona. Low Hypo First 23 diploid & Near AML-M2 2.6 7800 Remission Myeloid Leukemia Female Arab 5 cousin. tetraploid Normal B-ALL First 2.5 24 8.5 1500 Remission B cell Leukemia Male Arab –L1 cousin. High hyper Non Arab 25 B-ALL -L2 3 18200 Remission B cell anemia Male 6.5 diploid cona. Except six cases (Nos. 5, 7, 12, 13, 18, 24), the hemoglobin rate of the remaining patients ranges from 2.6 to 7.9, and is considered as anemic. Of 25 patients, 17 (68% ) had WBC of less than 10000 c/μl, five patients had 10000-50000 c/μl and three patients had e xtre me ly high WBC count, Table 1. Out of four Major ethnic groups liv ing in this province, including Persians (Farsis), Iranian Arabs (Arab) Bakhtiari Lurs (lurs), and Behbahanies, 14 Arab (56%), 9 Lurs (36%) and two Farsis (8%) are recorded. 3.2. Res ponse to Treatment Of these 25 leukemic cases, 23 (92%), ach ieved comp lete remission but with different resistant. Two patients (8%) d id not respond to treatment and survival, one of them with hypo-diploid karyotype had Philadelphia chro mosome, and other one had complex karyotype of hypo-diploid and near-haploid . Both of them were among AML patients with M3 and M4 subgroup, Table 3. Regarding hematolog ical parameters, cases with lower Hb (< 8 g m/dl) and high WBC (>50000/ mm3) showed a better remission rate. Cases with age < 5 years, male sex and couples with positive consanguinity also showed a better re mission rate, although not significant. 3.3. Clonal Abnormalities Of 25 patients studied, 17 (68%) cases with clonal plo idy abnormalities and eight cases (32%) of normal karyotype were recorded. A mong 17 cases with more than one abnormal karyptype, 10 cases (40%) were hyper-diploid,[six low (47-50 chro mosomes) and four highs (> 50 chromosomes) hyper-diploid], three cases (12%) were hypo-diploid (30-44 chro mosomes), Three cases (12%) were near tetra-ploid, (> 80 chro mosomes) Figures 1,2 and 3. and one patient was pseudo-diploid, Table 2. Although some of these patients are hypo-diploid (three cases), or pseudo-diploid (one case), most of them (92%) had good remission with treat ment protocols (U.K.C.C.S.G) for ALL, and (B.F.M) AML patients. Only two patients (8%) had no responses to treatment, both of which were among AML leukemic cases. Of 17 patients with abnormal karyotype, eleven B-cells ALL and five AM L with M 1 to M 5 subgroups were recorded. Classification of one of the patient could not be determined. Eight patients had complex karyotype with more than two clonal chro mosomal abnormalities. Details are available on req u es t. 48 Ali mohamad malekas gar et al.: Numerical Chromosomal Abnormalities in Patients With Acute Lymphoblastic and Myeloid Leukemia in Iran Ploidy group Normal Near haploid Low hypo diploid pseudo diploid Low hyper diploid High hyper diploid Near triploid Near tetraploid Tot al Table 2. Ploidy groups and number of patients in each group Chromosome number 46 23-29 30-44 46 47-50 50> 66-80 80> Number of Patients present in each group 8 -3 1 6 4 -3 25 P at ient s number 6-7-8-13-14-20-22-24 -- 3-15-18 11 2-5-9-16-19-21 1-10-12-25 -4-17-23 25 P ercent age 32% -12% 4% 24% 16% -12% 100% Table 3. Type of Samples in each leukemia subgroup Peripheral blood(PN) AML ALL 23 11-13-19-22 1 4 Sample and leukemia type Bone marrow(PN) ot hers AML ALL 4 & 12 1-3-10-18 2-5-6-7-8-9-14-15-16-17-2 0-21-24-25 2 4 14 Total No. of patients 25 25 PN=Patient,s numbe Figure 1. Patient No. 5 with low hyperdiploidy(48 chromosome) Figure 2. Patient No. 15 with low hypodiploidy (40 chromosom) Figure 3. Pationt No, 23 with near tetraploidy(83 chromosome) 4. Discussion Most of the leukemia patients have cytogenetical or mo lecular abnormality and it is shown that there are so me relations between chromosomal abnormalities and morphological and immunological characteristics of the cancer cells in these patients. More important are karyotype changes which show important prognosis without any relations to other variables like age, sex and primary leukocyte count, and so permits to differentiate between high risk and lo w risk patients at the time of d iagnosis for proper treatment. Cytogenetic analysis of 25 cases in our study shows 8 patients (32%) to have normal d iplo id karyotype, similar to many reports . Pseudo-diploid on the other hand were found in only one case (4%) which is much lo wer than the earlier reports which suggested that pseudo-diploid co mprised the largest cytogenetic group (41.5%) in childhood ALL[16]. This could be due to misclassification of pseudo-diploid karyotype by failure of detection of some submicroscopic genetic abnormalities at the conventional cytogenetic an aly s is . Low hypo-diploid karyotype (30-44 chro mosomes) were present in 12% of the our cases, which are h igher than those reported by others who considered hypo-diploidy to be a relatively uncommon (>9%) finding in ALL[17,18]. Many studies reported low percent of patients in hypo-diploid group, but some studies[19-20], including our study (12%) found much higher percent of the patient in this group with good remission. In studies in which only cytogenetic investigations are carried out, some hypo-diploid cells may not diagnosed correctly due to presence of many hyper-diploid cells and only after relapse of the disease and repeat investigation of these patients with FISH, or other advanced molecular methods, the true karyotype can be detected. Clinical M edicine and Diagnostics 2012, 2(5): 45-50 49 Hyper-dip loid (lo w + h igh hyper-diploid ) represented a majority of ALL cases in our study and many other authors have also reported same higher frequency[21,22]. The remission rates in our study cases were almost same among hypo-diploid, pseudo-diploid and hyper-diplo id groups, but the normal dip loid cases had better remission rate. Dip loid g roup was reported to have the best remission by some authors[19] although others considered it to be of an intermediate remission rate[23,24]. Response to treatment rates varied among chro mosome ploidy groups. The highest response rates were seen in patients with normal karyotypes and a modal number >50 chromosomes. In our study, after normal karyotype cases, we also found the best remission rate in this group. Hyper-dip loidy was found by some authors to have a good prognosis[25,26] unless associated with structural aberrations making it less favorable[19,27,28]. In our study, we had two resistant cases, one mixed numerical aberration (near haploid + low hypo-diploid) and the other one with low Hypo diploid, both of which were among AML subtype. Near-haplo id (< 30 chro mosomes) A LL, were not present in our case, except the one with mixed nu merical aberration (near haploid + low hypo-diploid) between two resistant patients. Near-haploid is a rare and unique subgroup associated with a very poor outcome. It may be underestimated being masked by a coexisting hyper-diploid line. In our study although any chromosome could be involved in tetrasomy, most of chromosomes especially 5,9,10, 12,18, 20,22 and X were duplicated mo re frequently. Of four Majors Ethnic groups in Khozestan province including Persians, Iran ian Arabs, Bakhtiari Lu rs, and Behbahanis, 14 Arab (56%), 9 Lurs (36%) and two Farsis (8%) are recorded. Prevalence of Arabs were significant in these four major ethnic groups, although it may be unreliab le due to small samp le size, Table 1. We could not find any data showing prevalence of leukemia in these Ethnic groups in Iran. The most common FA B type among our cases (48%) were L2 subtype with better remission compared to other immunophenotypes[29]. So me studies reported a poor prognosis associated with L2 and other studies reported that significance of L2 remained controversial[30]. Although full analy zing of karyotype spreads for determination of structural, nu merical and submicroscopic genetic abnormalities at the conventional cytogenetic analysis and its easier detection by the molecular and FISH technique is mandatory, but determination of only numerical chromosoma l changes (ploidy pattern) for typing of patients into different plo idy groups can also be useful as a primary step. Therefore we decided to conduct this study because of increasing number of ALL patients and need for immediate report for plo idy determination. We compare three standard methods including, overnight colcemid (ONC), flurodeo xy urid ine (FudR) and 24 hour protocols, with a modified direct culture method (12), and found the modified direct culture method to be easy and satisfactory for plo idy pattern determination in most (68%) cas es . 5. Conclusions We found excess number of patients having hypo-diploid karyotype but still response to treatment protocols were satisfactory. Variat ion in number of hypo-diploidy in different studies could be due to difference in ethnic group. Out of four different cultures methods used, we found the direct method to be satisfactory for ploidy analysis. ACKNOWLEDGEMENTS The authors of this article appreciate the authorities of Ahvaz Jundishapour university of med ical science for their financial support of this wo rk. We also wish to thanks Dr. Mohammad Housain Sarmast, the dean of Ahvaz Joundishaour University of Medical Science for his assistance and support. Special thanks to Dr. A LI Gasemi and Mrs. Nafiseh Esfandyari and all the me mbe rs of children Oncology unit of Shafa Houspital for their valuable contribution. REFERENCES [1] Young JL Jr, Ries LG, Silverberg E, Horm JW, M iller RW. Cancer incidence, survival and mortality for children younger than age 15 years. Cancer 1986;58:589 [2] Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100: 2292–302 [3] Pui C-H, Evans WE. Acute lymphoblastic leukemia. N Engl J M ed 1998;339:605–15 [4] Raimondi SC, Current status of cytogenetic research in childhood acute lymphoblastic leukemia. 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