- Email: [email protected]
P-036 Genomic analysis of myelodysplastic syndrome: Comparative analysis of peripheral blood and bone marrow clonal cells
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Poster Presentations – 12th International Symposium on Myelodysplastic Syndromes / Leukemia Research 37 S1 (2013) S1–S117
Conclusions: Our results indicate that AZA induces the upregulation of TERRA via hypomethylation of subtelomeric regions, thereby inhibiting telomerase in AZA-sensitive cell lines. Further studies using clinical samples are needed to clarify the possible role of telomere epigenetic modulation and AZA sensitivity in MDS patients.
P-034 ASXL1 mutations in myelodysplatic syndromes and their cooperation with additional gene mutations in the progression to secondary acute myeloid leukemia H. Chang 1 , Y.S. Shih 2 , T.H. Lin 2 , Y.H. Huang 2 , D.C. Liang 3 , S.T. Liang 3 , M.C. Kuo 1 , P.N. Wang 1 , J.H. Wu 1 , L.Y. Shih 4 . 1 Division of Hematology-Oncology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2 School of Medicine, Chang Gung University, Taoyuan, Taiwan; 3 Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan; 4 Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan Background: ASXL1 mutations have been described in both myelodyspolastic syndromes (MDS) and acute myeloid leukemia (AML). Introduction: There is mounting evidence suggesting that epigenetic genes are involved in leukemogenesis. ASXL1 mutation is one of the most commonly identified gene mutations of epigenetic modifiers in MDS and AML. The role of ASXL1 mutations in transformation from MDS to secondary AML (sAML) is unclear. Purpose: We aimed to investigate the clinical significance of ASXL1 mutations in MDS and looked into the mutational evolution of ASXL1 with its cooperation genes in the transformation from MDS to sAML. Materials and Methods: ASXL1 mutations were investigated in 131 patients with de novo MDS. Paired MDS/sAML samples were available for 58 patients. Mutational analysis of ASXL1 was performed by PCR-based assays followed by direct sequencing. Additional 20 known gene mutations in myeloid neoplasms were also examined in patients carrying ASXL1 mutations to determine the role of cooperating mutations with ASXL1 in progression to sAML. Results: Among 131 de novo MDS patients, ASXL1 mutations were found in 19 (14.5%) cases. Compared with the wild-type group, ASXL1-mutated patients had a stronger male predominance (17 out of 19 patients, P=0.018) and fewer circulating blasts (0.37±0.89% vs. 1.3±2.7%, P=0.003). ASXL1-mutated and -unmutated patients had no difference in hemoglobin levels, white blood cell counts, platelet counts, karyotypes, WHO subtypes, bone marrow blasts, IPSS-R or risk to sAML. ASXL1 mutations had no substantial impact on overall survival (P=0.434) or time to sAML transformation (P= 0.449). Of the 58 paired samples, ASXL1 mutations were identified in 8 cases at diagnosis of MDS, all of which were also detected at the time of sAML progression while ASXL1 mutations were newly identified in sAML samples in 2 cases. Progression to sAML was accompanied by additional gene mutations including FLT3-ITD, PTPN11, C-CBL, CEBPα, RUNX1, DNMT3A, TET2, IDH2 and EZH2. In total, 14 additional mutations were identified in 6 out of the 10 cases carrying ASXL1 mutations at sAML. RUNX1 was the most commonly mutated (N=4), followed by CEBPα (N=2) and others in single cases. These mutations were found at the diagnosis of MDS (8 mutations in 5 cases) or newly appeared at the time of progression to sAML (6 mutations in 4 cases). Conclusions: Our results demonstrated that clonal evolution of ASXL1 mutations may occur and cooperation of additional gene mutations are frequently detected in patients harboring ASXL1 mutations in progression of MDS to sAML. Grant support: This work was supported by NHRI-EX101-10003NI, DOH101-TD-C-111-006 and MMH-E-101-09, Taiwan.
P-035 Marked upregulation of Bcl-2 and low expression of Beclin 1 is associated with MDS and disease progression Y. Wang, S. Wan, J. Cen, R. Zhang, X. Qi, J. Pan, D. Liu, L. Yao, Y. Chen, Z. Chen. Jiangsu Institute of Hematology, 1st Affiliated Hospital Soochow University, Suzhou, China Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis. Introduction: As the first identified mammalian autophagy effector, Beclin 1 is essential for the initiation and activation of autophagy. Beclin 1 possess a novel Bcl-2 homology region-3 (BH3) domain. Bcl-2 antiapoptotic proteins inhibit Beclin 1-mediated autophagy. Purpose: To determine the role of Beclin 1 and Bcl-2 in disease progression of MDS Materials and Methods: We detected the expression levels of these two genes at both transcriptional and protein levels in bone marrow mononuclear cells (BMMCs) cells prepared from 147 patients with MDS, 12 patients with secondary acute myeloid leukemia following myelodysplastic syndrome (s-AML), 81 patients with de novo acute myeloid leukemia (d-AML) and 16 non-malignant anemia by using quantitative real-time PCR, immuno-fluorescent staining and western blotting. Results: The expression level of Beclin 1 and Bcl-2 was highly correlated with the subtype of MDS. Bcl-2 expressed at a much higher level in RAEB-1, RAEB-2, s-AML and d-AML than in normal control, and increased during disease progression. On the contrary, the expression of Beclin 1 was significantly higher in low-risk MDS (WPSS score≤2) and non-malignant anemia as control than that in highrisk MDS, s-AML (p<0.01) and d-AML at both mRNA and protein levels. Additionally, the score by WPSS was negatively correlated with the expression level of Beclin1 gene in MDS patients. Interestingly, these levels were remarkably different between patients with s-AML and those with d-AML. Conclusions: A low level of Beclin 1 and high Bcl-2 expression in BMMCs cells are distinctive molecular features of high-risk MDS and s-AML. Marked upregulation of Bcl-2 and low expression of Beclin 1 may contribute to genetic instability and disease progression of MDS, implying the dynamic balance between apoptosis and the Beclinmediated autophagy may affect in the mechanism of the progression of MDS to AML. Clinically, a low expression of Beclin 1, associated with high Bcl-2, may predict a malignant phenotype and disease progression in MDS.
P-036 Genomic analysis of myelodysplastic syndrome: Comparative analysis of peripheral blood and bone marrow clonal cells S.Y. Kim 1 , S.N. Park 2 , J. Kwon 2 , J.A. Kim 1 , Q. Choi 1 , S.M. Hwang 1 , K.S. Ahn 2 , S.S. Yoon 3 , D.S. Lee 1 . 1 Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea; 2 Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; 3 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea Background: Myelodysplastic syndrome (MDS) is a heterogeneous disease characterized by multiple genetic and epigenetic alterations associated with impaired hematopoietic differentiation. Using next generation sequencing, many important new somatic mutations underlying the pathogenesis of MDS have been uncovered. Introduction: For detection of these mutations, bone marrow (BM) specimens are commonly evaluated. However, for monitoring disease, to perform BM aspiration repeatedly for genetic testing may be difficult. Although sampling of peripheral blood (PB) is less painful
Poster Presentations – 12th International Symposium on Myelodysplastic Syndromes / Leukemia Research 37 S1 (2013) S1–S117
for patients, it is not certain whether hematopoietic cells circulating in PB harbor same mutations found in BM. Purpose: The aim of this study is to investigate somatic mutations in BM and PB cells of MDS patients, and to identify useful genetic markers for diagnosing and monitoring MDS. Materials and Methods: Paired PB and BM specimens were obtained from 5 patients. One patient was diagnosed as refractory cytopenia with multilineage dysplasia (RCMD), 2 were diagnosed as refractory cytopenia with excess blasts (RAEB), and 2 patients had acute myeloid leukemia (AML) evolved from previously diagnosed RAEB. Saliva cells were also collected from each patient to obtain germline DNA. Whole exome sequencing was performed using Illumina HiSeq 2000. Putative mutations in BM and PB samples of each patient were analyzed in comparison to germline samples. Results: Multiple somatic mutations were detected, including genes known to be associated with oncogenesis such as PTPN11, TP53, and RB1. In the comparison of mutations found in PB and BM, the mutation profiles were not completely overlap between these paired samples. Mutations found in PB tended to have lower frequency than those found in BM, reflecting lower tumor burden. There were several mutations found in PB, which were not emerged as significant mutation in BM at first screening, which may reflect the clonal cells distribute differently between BM and PB. Conclusions: The analysis of somatic mutations in patients with MDS can provide useful targets for the development of new therapeutic approaches. The genetic analysis of PB from MDS patients can provide useful information for pathogenesis of MDS and selecting useful monitoring targets of disease.
P-037 Association between HLA and development of myelodysplastic syndrome in children A. Chumak 1 , L. Lebedeva 1 , T. Pukhlikova 1 , T. Astrelina 1 , M. Yakovleva 1 , Z. Dyshlevaya 2 , A. Arkhipova 2 . 1 Moscow Department of Public Health, Moscow Stem Cell Bank, Moscow, Russia; 2 Health Ministry of Russia, Russian Children’s Clinical Hospital, Moscow, Russia Background: Myelodysplastic syndrome (MDS) is the disorder, which can not remain unrecognized by immune system due to participation of HLA-molecules. To date, the association between immunogenetic factors and MDS is well established. Introduction: The key event in the pathogenesis of MDS is the appearance, survival and progression of pathological clone of hematopoietic stem cells. The efficiency of removing of pathological clone depends on the intensity of the immune response, which determined by HLA-molecules. Purpose: To investigate the relationship between HLA and development of MDS in children. Materials and Methods: We investigated the results of HLA-typing of 39 children with MDS, treated in clinics of Moscow. Among patients with MDS there were 19 boys and 20 girls aged from 1.5 to 17 (mean 7.8±4.65). The control group consisted of 1700 umbilical cord blood samples of conditionally healthy donors. All investigated subjects were related to the Eastern European population. The HLAtyping was performed by SSO and PCR-SSP methods. Statistical data processing was carried out using the following tests: the frequency (f) of HLA I and II class alleles, the chi-square criterion with Yates correction, the p value (p<0.05), the Odds Ratio (OR) and the Confidential Intervals (CI). Results: We compared the frequencies of HLA I and II class alleles in children with MDS and in the control group to define the association between HLA and predisposition or sustainability to MDS. Among patients with MDS we obtained a high frequency of DRB1*14 (OR=4.0, CI 1.36-10.3, P=0.008), B*40 (OR=2.88, CI 1.21-6.26, P=0.015), A*11
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(OR=2.74, CI 1.25-5.66, P=0.011), A*26 (OR=2.59, CI 1.09-5.62, P=0.03) and a low frequency of DQB1*02 (OR=0.33, CI 0.12- 0.84, P=0.03) in comparison with the control group (Table 1). Table 1. The frequency of HLA class I and II alleles in children with MDS and in the control group, p<0,05 Allele groups of HLA A*11 A*26 B*40 DRB1*14 DQB1*02
Control group (n=1700)
Children with MDS (n=39)
p
0,059 0,048 0,043 0,018 0,197
0,148 0,121 0,108 0,065 0,089
0,006 0,01 0,03 0,03 0,03
Conclusions: Thus, the results suggest the DRB1*14, B*40, A*11, A*26 are markers of predisposition to MDS in children. The greatest risk of MDS in children associated with a marker DRB1*14, which increases the risk in 4 times. Allele group DQB1*02 associated with sustainability to the MDS in children.
P-038 Unbalanced translocation t(1;12)(q10;q10): A state of bone marrow insufficiency due to trisomy 1q? A. Dulau Florea 1 , J. Filicko-O’Hara 2 , J. Sprandio 3 , J. Gong 1 , G. Gulati 1 , E. Besa 2 , R. Bajaj 1 . 1 Pathology, Thomas Jefferson University Hospital, Philadaelphia, USA; 2 Medical Oncology, Thomas Jefferson University Hospital, Philadaelphia, USA; 3 Hematology/Medical Oncology, Thomas Jefferson University Hospital, Philadaelphia, USA Background: Hypocellular myelodysplastic syndromes (hMDS) are characterized by bone marrow (BM) failure as a result of both inhibition of normal progenitors and ineffective hematopoiesis of abnormal clones. Although immune processes mediated by T-cell response have been extensively studied in hMDS, little is known about the cytogenetic abnormalities implicated in its pathogenesis. Complete or partial trisomy 1q is a recurrent aberration in Fanconi anemia, a constitutional bone marrow failure with increased susceptibility to myelodysplasia (MDS) and acute leukemia. Trisomy 1q is commonly the result of unbalanced translocations between chromosome 1 and different partners. Introduction: Here, we report the case of a 60 year-old man with persistent BM failure after chemotherapy for acute myeloid leukemia with myelodysplasia-related changes and trisomy 1q. Trisomy 1q resulted from an unbalanced translocation between 1q10 and 12q10. Purpose: To evaluate the prognostic impact of 1q gain on BM hematopoiesis. Materials and Methods: CBC was performed by automated hematology analyzer. Peripheral smears and BM morphology were evaluated by 2 hematopathologists. BM cells were analyzed by flow cytometry and cytogenetics, which included conventional karyotype and fluorescence in-situ hybridization (FISH). Results: Peripheral blood revealed pancytopenia and 5% blasts. The BM was hypocellular (30%) with 31% myeloblasts and dysplastic morphology. The diagnosis was acute myeloid leukemia with myelodysplasiarelated changes (AML-MRC). Cytogenetics identified an abnormal male karyotype: 46,XY,+1, der(1;12)(q10;q10)[5]/47,idem,+8[14]/46,XY[1]. All abnormal cells contained an unbalanced rearrangement involving chromosomes 1 and 12, resulting in gain of the long arm of chromosome 1 and loss of the short arm of chromosome 12. Trisomy 8 was present in a subset of cells and was not detected in subsequent marrows. After induction and consolidation chemotherapy, at day 31, there was no morphologic and immunophenotypic evidence of leukemia,
Poster Presentations – 12th International Symposium on Myelodysplastic Syndromes / Leukemia Research 37 S1 (2013) S1–S117
Conclusions: Our results indicate that AZA induces the upregulation of TERRA via hypomethylation of subtelomeric regions, thereby inhibiting telomerase in AZA-sensitive cell lines. Further studies using clinical samples are needed to clarify the possible role of telomere epigenetic modulation and AZA sensitivity in MDS patients.
P-034 ASXL1 mutations in myelodysplatic syndromes and their cooperation with additional gene mutations in the progression to secondary acute myeloid leukemia H. Chang 1 , Y.S. Shih 2 , T.H. Lin 2 , Y.H. Huang 2 , D.C. Liang 3 , S.T. Liang 3 , M.C. Kuo 1 , P.N. Wang 1 , J.H. Wu 1 , L.Y. Shih 4 . 1 Division of Hematology-Oncology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2 School of Medicine, Chang Gung University, Taoyuan, Taiwan; 3 Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan; 4 Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan Background: ASXL1 mutations have been described in both myelodyspolastic syndromes (MDS) and acute myeloid leukemia (AML). Introduction: There is mounting evidence suggesting that epigenetic genes are involved in leukemogenesis. ASXL1 mutation is one of the most commonly identified gene mutations of epigenetic modifiers in MDS and AML. The role of ASXL1 mutations in transformation from MDS to secondary AML (sAML) is unclear. Purpose: We aimed to investigate the clinical significance of ASXL1 mutations in MDS and looked into the mutational evolution of ASXL1 with its cooperation genes in the transformation from MDS to sAML. Materials and Methods: ASXL1 mutations were investigated in 131 patients with de novo MDS. Paired MDS/sAML samples were available for 58 patients. Mutational analysis of ASXL1 was performed by PCR-based assays followed by direct sequencing. Additional 20 known gene mutations in myeloid neoplasms were also examined in patients carrying ASXL1 mutations to determine the role of cooperating mutations with ASXL1 in progression to sAML. Results: Among 131 de novo MDS patients, ASXL1 mutations were found in 19 (14.5%) cases. Compared with the wild-type group, ASXL1-mutated patients had a stronger male predominance (17 out of 19 patients, P=0.018) and fewer circulating blasts (0.37±0.89% vs. 1.3±2.7%, P=0.003). ASXL1-mutated and -unmutated patients had no difference in hemoglobin levels, white blood cell counts, platelet counts, karyotypes, WHO subtypes, bone marrow blasts, IPSS-R or risk to sAML. ASXL1 mutations had no substantial impact on overall survival (P=0.434) or time to sAML transformation (P= 0.449). Of the 58 paired samples, ASXL1 mutations were identified in 8 cases at diagnosis of MDS, all of which were also detected at the time of sAML progression while ASXL1 mutations were newly identified in sAML samples in 2 cases. Progression to sAML was accompanied by additional gene mutations including FLT3-ITD, PTPN11, C-CBL, CEBPα, RUNX1, DNMT3A, TET2, IDH2 and EZH2. In total, 14 additional mutations were identified in 6 out of the 10 cases carrying ASXL1 mutations at sAML. RUNX1 was the most commonly mutated (N=4), followed by CEBPα (N=2) and others in single cases. These mutations were found at the diagnosis of MDS (8 mutations in 5 cases) or newly appeared at the time of progression to sAML (6 mutations in 4 cases). Conclusions: Our results demonstrated that clonal evolution of ASXL1 mutations may occur and cooperation of additional gene mutations are frequently detected in patients harboring ASXL1 mutations in progression of MDS to sAML. Grant support: This work was supported by NHRI-EX101-10003NI, DOH101-TD-C-111-006 and MMH-E-101-09, Taiwan.
P-035 Marked upregulation of Bcl-2 and low expression of Beclin 1 is associated with MDS and disease progression Y. Wang, S. Wan, J. Cen, R. Zhang, X. Qi, J. Pan, D. Liu, L. Yao, Y. Chen, Z. Chen. Jiangsu Institute of Hematology, 1st Affiliated Hospital Soochow University, Suzhou, China Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis. Introduction: As the first identified mammalian autophagy effector, Beclin 1 is essential for the initiation and activation of autophagy. Beclin 1 possess a novel Bcl-2 homology region-3 (BH3) domain. Bcl-2 antiapoptotic proteins inhibit Beclin 1-mediated autophagy. Purpose: To determine the role of Beclin 1 and Bcl-2 in disease progression of MDS Materials and Methods: We detected the expression levels of these two genes at both transcriptional and protein levels in bone marrow mononuclear cells (BMMCs) cells prepared from 147 patients with MDS, 12 patients with secondary acute myeloid leukemia following myelodysplastic syndrome (s-AML), 81 patients with de novo acute myeloid leukemia (d-AML) and 16 non-malignant anemia by using quantitative real-time PCR, immuno-fluorescent staining and western blotting. Results: The expression level of Beclin 1 and Bcl-2 was highly correlated with the subtype of MDS. Bcl-2 expressed at a much higher level in RAEB-1, RAEB-2, s-AML and d-AML than in normal control, and increased during disease progression. On the contrary, the expression of Beclin 1 was significantly higher in low-risk MDS (WPSS score≤2) and non-malignant anemia as control than that in highrisk MDS, s-AML (p<0.01) and d-AML at both mRNA and protein levels. Additionally, the score by WPSS was negatively correlated with the expression level of Beclin1 gene in MDS patients. Interestingly, these levels were remarkably different between patients with s-AML and those with d-AML. Conclusions: A low level of Beclin 1 and high Bcl-2 expression in BMMCs cells are distinctive molecular features of high-risk MDS and s-AML. Marked upregulation of Bcl-2 and low expression of Beclin 1 may contribute to genetic instability and disease progression of MDS, implying the dynamic balance between apoptosis and the Beclinmediated autophagy may affect in the mechanism of the progression of MDS to AML. Clinically, a low expression of Beclin 1, associated with high Bcl-2, may predict a malignant phenotype and disease progression in MDS.
P-036 Genomic analysis of myelodysplastic syndrome: Comparative analysis of peripheral blood and bone marrow clonal cells S.Y. Kim 1 , S.N. Park 2 , J. Kwon 2 , J.A. Kim 1 , Q. Choi 1 , S.M. Hwang 1 , K.S. Ahn 2 , S.S. Yoon 3 , D.S. Lee 1 . 1 Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea; 2 Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; 3 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea Background: Myelodysplastic syndrome (MDS) is a heterogeneous disease characterized by multiple genetic and epigenetic alterations associated with impaired hematopoietic differentiation. Using next generation sequencing, many important new somatic mutations underlying the pathogenesis of MDS have been uncovered. Introduction: For detection of these mutations, bone marrow (BM) specimens are commonly evaluated. However, for monitoring disease, to perform BM aspiration repeatedly for genetic testing may be difficult. Although sampling of peripheral blood (PB) is less painful
Poster Presentations – 12th International Symposium on Myelodysplastic Syndromes / Leukemia Research 37 S1 (2013) S1–S117
for patients, it is not certain whether hematopoietic cells circulating in PB harbor same mutations found in BM. Purpose: The aim of this study is to investigate somatic mutations in BM and PB cells of MDS patients, and to identify useful genetic markers for diagnosing and monitoring MDS. Materials and Methods: Paired PB and BM specimens were obtained from 5 patients. One patient was diagnosed as refractory cytopenia with multilineage dysplasia (RCMD), 2 were diagnosed as refractory cytopenia with excess blasts (RAEB), and 2 patients had acute myeloid leukemia (AML) evolved from previously diagnosed RAEB. Saliva cells were also collected from each patient to obtain germline DNA. Whole exome sequencing was performed using Illumina HiSeq 2000. Putative mutations in BM and PB samples of each patient were analyzed in comparison to germline samples. Results: Multiple somatic mutations were detected, including genes known to be associated with oncogenesis such as PTPN11, TP53, and RB1. In the comparison of mutations found in PB and BM, the mutation profiles were not completely overlap between these paired samples. Mutations found in PB tended to have lower frequency than those found in BM, reflecting lower tumor burden. There were several mutations found in PB, which were not emerged as significant mutation in BM at first screening, which may reflect the clonal cells distribute differently between BM and PB. Conclusions: The analysis of somatic mutations in patients with MDS can provide useful targets for the development of new therapeutic approaches. The genetic analysis of PB from MDS patients can provide useful information for pathogenesis of MDS and selecting useful monitoring targets of disease.
P-037 Association between HLA and development of myelodysplastic syndrome in children A. Chumak 1 , L. Lebedeva 1 , T. Pukhlikova 1 , T. Astrelina 1 , M. Yakovleva 1 , Z. Dyshlevaya 2 , A. Arkhipova 2 . 1 Moscow Department of Public Health, Moscow Stem Cell Bank, Moscow, Russia; 2 Health Ministry of Russia, Russian Children’s Clinical Hospital, Moscow, Russia Background: Myelodysplastic syndrome (MDS) is the disorder, which can not remain unrecognized by immune system due to participation of HLA-molecules. To date, the association between immunogenetic factors and MDS is well established. Introduction: The key event in the pathogenesis of MDS is the appearance, survival and progression of pathological clone of hematopoietic stem cells. The efficiency of removing of pathological clone depends on the intensity of the immune response, which determined by HLA-molecules. Purpose: To investigate the relationship between HLA and development of MDS in children. Materials and Methods: We investigated the results of HLA-typing of 39 children with MDS, treated in clinics of Moscow. Among patients with MDS there were 19 boys and 20 girls aged from 1.5 to 17 (mean 7.8±4.65). The control group consisted of 1700 umbilical cord blood samples of conditionally healthy donors. All investigated subjects were related to the Eastern European population. The HLAtyping was performed by SSO and PCR-SSP methods. Statistical data processing was carried out using the following tests: the frequency (f) of HLA I and II class alleles, the chi-square criterion with Yates correction, the p value (p<0.05), the Odds Ratio (OR) and the Confidential Intervals (CI). Results: We compared the frequencies of HLA I and II class alleles in children with MDS and in the control group to define the association between HLA and predisposition or sustainability to MDS. Among patients with MDS we obtained a high frequency of DRB1*14 (OR=4.0, CI 1.36-10.3, P=0.008), B*40 (OR=2.88, CI 1.21-6.26, P=0.015), A*11
S39
(OR=2.74, CI 1.25-5.66, P=0.011), A*26 (OR=2.59, CI 1.09-5.62, P=0.03) and a low frequency of DQB1*02 (OR=0.33, CI 0.12- 0.84, P=0.03) in comparison with the control group (Table 1). Table 1. The frequency of HLA class I and II alleles in children with MDS and in the control group, p<0,05 Allele groups of HLA A*11 A*26 B*40 DRB1*14 DQB1*02
Control group (n=1700)
Children with MDS (n=39)
p
0,059 0,048 0,043 0,018 0,197
0,148 0,121 0,108 0,065 0,089
0,006 0,01 0,03 0,03 0,03
Conclusions: Thus, the results suggest the DRB1*14, B*40, A*11, A*26 are markers of predisposition to MDS in children. The greatest risk of MDS in children associated with a marker DRB1*14, which increases the risk in 4 times. Allele group DQB1*02 associated with sustainability to the MDS in children.
P-038 Unbalanced translocation t(1;12)(q10;q10): A state of bone marrow insufficiency due to trisomy 1q? A. Dulau Florea 1 , J. Filicko-O’Hara 2 , J. Sprandio 3 , J. Gong 1 , G. Gulati 1 , E. Besa 2 , R. Bajaj 1 . 1 Pathology, Thomas Jefferson University Hospital, Philadaelphia, USA; 2 Medical Oncology, Thomas Jefferson University Hospital, Philadaelphia, USA; 3 Hematology/Medical Oncology, Thomas Jefferson University Hospital, Philadaelphia, USA Background: Hypocellular myelodysplastic syndromes (hMDS) are characterized by bone marrow (BM) failure as a result of both inhibition of normal progenitors and ineffective hematopoiesis of abnormal clones. Although immune processes mediated by T-cell response have been extensively studied in hMDS, little is known about the cytogenetic abnormalities implicated in its pathogenesis. Complete or partial trisomy 1q is a recurrent aberration in Fanconi anemia, a constitutional bone marrow failure with increased susceptibility to myelodysplasia (MDS) and acute leukemia. Trisomy 1q is commonly the result of unbalanced translocations between chromosome 1 and different partners. Introduction: Here, we report the case of a 60 year-old man with persistent BM failure after chemotherapy for acute myeloid leukemia with myelodysplasia-related changes and trisomy 1q. Trisomy 1q resulted from an unbalanced translocation between 1q10 and 12q10. Purpose: To evaluate the prognostic impact of 1q gain on BM hematopoiesis. Materials and Methods: CBC was performed by automated hematology analyzer. Peripheral smears and BM morphology were evaluated by 2 hematopathologists. BM cells were analyzed by flow cytometry and cytogenetics, which included conventional karyotype and fluorescence in-situ hybridization (FISH). Results: Peripheral blood revealed pancytopenia and 5% blasts. The BM was hypocellular (30%) with 31% myeloblasts and dysplastic morphology. The diagnosis was acute myeloid leukemia with myelodysplasiarelated changes (AML-MRC). Cytogenetics identified an abnormal male karyotype: 46,XY,+1, der(1;12)(q10;q10)[5]/47,idem,+8[14]/46,XY[1]. All abnormal cells contained an unbalanced rearrangement involving chromosomes 1 and 12, resulting in gain of the long arm of chromosome 1 and loss of the short arm of chromosome 12. Trisomy 8 was present in a subset of cells and was not detected in subsequent marrows. After induction and consolidation chemotherapy, at day 31, there was no morphologic and immunophenotypic evidence of leukemia,