Mitochondria are important intracellular organelles that produce energy for cellular development, differentiation, and growth. Mitochondrial DNA (mtDNA) presents a 10- to 20-fold higher susceptibility to genetic mutations owing to the lack of introns and histone proteins. The mtDNA repair system is relatively inefficient, rendering it vulnerable to reactive oxygen species (ROS) produced during ATP synthesis within the mitochondria, which can then target the mtDNA. Under conditions of chronic inflammation and excess stress, increased ROS production can overwhelm the antioxidant system, resulting in mtDNA damage. This paper reviews recent literature describing the pathophysiological implications of oxidative stress, mitochondrial dysfunction, and mitochondrial genome aberrations in aging hematopoietic stem cells, bone marrow failure syndromes, hematological malignancies, solid organ cancers, chronic inflammatory diseases, and other diseases caused by exposure to environmental hazards.

Th e frequency of simultaneous paroxysmal nocturnal hemoglobinuria (PNH) clones in patients with myelodysplastic syndrome (MDS) ranges from 12.8 to 15.5% [1]. Th e clinical signifi cance of PNH-type cells in MDS is controversial. One study reports that the presence of an increased number of PNH-type cells was predictive of a good response to immunosuppressive therapy and a favorable prognosis among patients with marrow failure [2]. However, another study reports that patients with MDS of worse prognosis more strongly expressed the PNH clone compared to patients with refractive anemia (RA) and refractory anemia with ringed sideroblasts (RARS), who had a better prognosis [1]. Marrow failure, especially MDS, occasionally shows thrombocytosis due to an overlap of myeloproliferative neoplasms (MPNs) and association with some MDS subtypes. Classically, thrombocytosis has been associated with the MDS subtypes RARS and 5q Ϫ syndrome. Here, we report an extremely rare and interesting case of PNH-MDS associated with marked thrombocytosis and clonal chromosomal abnormality.A 51-year-old man suff ered from fever and pleural eff usion with left chest pain, which persisted for 1 month despite antimicrobial treatment. Th e patient was a heavy alcohol drinker and smoker. Physical examination revealed anemic conjunctiva, crackles in the left lung and splenomegaly. At admission, the following hematologic features were found: hemoglobin 8.3 g/dL, hematocrit 25.9%, mean corpuscular volume 103.8 fL, leukocyte count 10 300/ μ L with 2.6% basophils, 10.8% monocytes, and a platelet count of 532 000/ μ L. Serum levels of vitamin B12 and folate were in the normal ranges. Serum iron (16 μ g/dL) and total iron binding capacity (166 μ g/dL) levels were decreased, and the ferritin level (496.4 ng/dL) was elevated. Th e coagulation profi le showed a slightly prolonged prothrombin time (16.5 s, international normalized ratio 1.50, 46.9%), prolonged activated partial thromboplastin time (51.6 s), and elevated levels of D-dimer (0.74 mg/L), fi brin degradation product (10.0 μ g/mL) and fi brinogen (474.3 mg/dL). Th e C-reactive protein level (1.98 mg/dL) and lactate dehydrogenase (LDH) activity (1545 U/L) were also elevated. Laboratory parameters for evaluating hemolysis were in the normal ranges: total bilirubin 0.66 mg/dL, direct bilirubin 0.22 mg/ dL, haptoglobin 63.7 mg/dL, no abnormal urine analysis and negative for occult blood. Computed tomography scans of the chest showed empyema with pleural eff usion in the left hemithorax. Examination of pleural fl uid revealed a bloody color and leukocytes 1382/ μ L (96% lymphocytes), protein 5.0 g/dL (serum protein 6.5 mg/dL), albumin 2.9 g/dL (serum albumin 3.6 mg/dL), LDH activity 1457 U/L (serum LDH 1545 U/L), adenosine deaminase 59.8 IU/L and glucose 86 mg/dL (serum glucose 99 mg/dL). Screening for tuberculosis using the QuantiFERON assay was positive. Th erefore, tuberculosis pleurisy was suspected and the patient was treated for tuberculosis. Peripheral blood smears revealed moderate macrocytic...

3958 Background: Recently, a striking example of the effects on acquired somatic mutations in splicing factors such as SF3B1, U2AF1, and SRSF2 has been described. The sequencing of the DNA from abnormal blood cells from patients with several types of leukemia such as AML, CLL, CMML, pre-leukemic syndromes, and MDS, has shown that a high proportion of these cases are associated with somatic mutations in spliceosomal proteins. Also, evidence of cancer-specific alternative splicing and oncogenic somatic mutations in spliceosome subunits has been steadily growing. However, there is not much research regarding aberrant splicing pathways in Multiple myeloma (MM) patients. Therefore, we tried to investigate the presence and prognostic implication of mutation of the SF3B1 and U2AF1 protein in these patients in South Korea. Materials and Methods: We examined a cohort of 87 MM patients and 100 healthy controls for somatic mutations in SF3B1, U2AF1 and SRSF2 by using direct sequencing method. The medical records were reviewed for age, sex, plasma cell percentage, serum M protein, immunoglobulin level, free light chain ratio, calcium, creatinine, hemoglobin, bone lesion, albumin, beta 2 microglobulin, lactate dehydrogenase, treatment outcome, and so on. The collected data was analyzed by SPSS for Windows version 18.0. We performed Pearson's chi-square tests, one way ANOVA analysis, and Student t-test. Survival rates of myeloma patients according to the result of SF3B1, U2AF1 and SRSF2 sequencing were analyzed using Kaplan-Meier log-rank test. Results: Our 87 MM patients showed no mutation including known recurrent ones in SF3B1, U2AF1 and SRSF2 genes. However, the patients displayed 39198T>T/C polymorphism (70.1%) in exon 18 of SF3B1, 8345T>T/G polymorphism (13.8%) in exon 2 of U2AF1 and 5399C/T polymorphism (100%) in exon 1 of SRSF2. In the entire cohort, the number of patients with no polymorphism, one polymorphism, two polymorphisms and three polymorphisms was counted up to 0%, 24.1%, 67.8% and 8.0%, respectively. The T/C polymorphism at position 39198 of SF3B1 exon 18 and the T/G polymorphism at position 8345 of U2AF1 exon 2 were analyzed by allele-specific PCR using normal control. Results in 100 normal controls, polymorphism of SF3B1 exon 18 was taken into account of 82.0%, the remaining is non polymorphism while U2AF1 exon 2 showed 10.0% polymorphism and 90.0% non polymorphism. Sex (p=0.048) and free light chain ratio (p=0.002) showed significant results according to polymorphism status while other clinical characteristics were not associated. The patient with polymorphisms in both SF3B1 and U2AF1 had worse overall survival (P=0.042) and disease-free survival (P<0.01), compared to patients without polymorphism. Conclusion: Our results show no recurrent SF3B1, U2AF1 and SRSF2 mutations in MM patients rather polymorphisms in SF3B1 and U2AF1 gene were significantly implicated in the prediction of poor prognosis. Disclosures: No relevant conflicts of interest to declare.

4950 Background: Myelodysplastic syndrome (MDS) is an hematopoietic stem cells (HSCs) disorder, leading to malignant cells that ultimately grow uncontrollably. Somatic mutations of spliceosomal gene such as SF3B1, U2AF1 and SRSF2 has been widely described in MDS and other hematological malignancies. Many reports state that hematopoietic malignancies mostly result from somatic mutations in HSCs in the bone marrow. Some functional studies have been performed and have shown that a high proportion of these cases are associated with somatic mutations in spliceosomal proteins. Also, such kinds of mutation are hallmarks of dominantly acting and growing specific cancer. Many efforts have been made to unravel the mutation considered disease background of MDS. Genotype–phenotype associations have been demonstrated for somatic spliceosomal gene mutation in MDS with ring sideroblasts but there is not much research regarding aberrant splicing pathways in MDS without harboring ring sideroblast. Therefore, this study investigated the prevalence and prognostic implication of the SF3B1, U2AF1 and SRSF2 splice gene mutation in these patients in Korea. Materials and Methods: The study cohort of 92 MDS patients was examined for somatic mutations in SF3B1, U2AF1 and SRSF2 splicing gene using direct sequencing method. The clinical and hematologic data were also recorded. The collected data was analyzed by SPSS for Windows version 18. 0. Pearson's chi-square tests, one way ANOVA analysis, and Student t-test were performed. Survival rates of multiple myeloma patients according to the mutation result of SF3B1, U2AF1 and SRSF2 splicing gene were analyzed using Kaplan-Meier log-rank test. Results: Our 92 MDS patients showed recurrent mutation and polymorphisms. Mutations in K666N, H662Q and K700E of SF3B1; S34T, S34P and Q157P of U2AF1; P95H, P95R and P95L of SRSF2 were found in 8 (8. 7%), 6 (6. 5%), and 11 (11. 9%) patients, respectively. The patients displayed 39198T>T/C polymorphism (88. 0%) in exon 18 of SF3B1, 8345T>T/G polymorphism (7. 6%) in exon 2 of U2AF1 and 5399C/T polymorphism (100%) in exon 1 of SRSF2. In the entire cohort, the number of patients with no polymorphism, one polymorphism, two polymorphisms and three polymorphisms was counted up to 0%, 12%, 80. 4% and 7. 6%, respectively. The T/C polymorphism at position 39198 of SF3B1 exon 18 and the T/G polymorphism at position 8345 of U2AF1 exon 2 were analyzed by allele-specific PCR using normal control. Results in 100 normal controls, polymorphism of SF3B1 exon 18 was taken into account of 82. 0%, the remaining is non polymorphism while U2AF1 exon 2 showed 10. 0% polymorphism and 90. 0% non polymorphism. The patient with either polymorphisms or mutations in both SF3B1, U2AF1 and SRSF2 had no effect on overall survival and disease-free survival. Conclusion: Our results show that mutation rate of SF3B1, U2AF1 and SRSF2 splice gene in Korean MDS patients without harboring ring sideroblast displayed relatively rare and infrequent molecular event. Moreover, alteration of SF3B1, U2AF1 and SRSF2 splice gene was not significantly implicated in the clinical outcomes and prognosis. Disclosures: No relevant conflicts of interest to declare.