Pig‐a gene mutations in bone marrow granulocytes of procarbazine‐treated F344 rats

2021 ◽  
Vol 62 (4) ◽  
pp. 265-272
Author(s):  
Azra Dad ◽  
Javier R. Revollo ◽  
Mason G. Pearce ◽  
Page B. McKinzie ◽  
Robert H. Heflich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Gene Mutations ◽  
F344 Rats ◽  
Bone Marrow Granulocytes

Analysis of mutation in the rat Pig-a assay: II. Studies with bone marrow granulocytes

2018 ◽  
Vol 59 (8) ◽  
pp. 733-741 ◽  
Author(s):  
Azra Dad ◽  
Javier R. Revollo ◽  
Dayton M. Petibone ◽  
Mason G. Pearce ◽  
Robert H. Heflich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Granulocytes

scholarly journals Krüppel-like factor 3 inhibition by mutated lncRNA Reg1cp results in human high bone mass syndrome

2019 ◽  
Vol 216 (8) ◽  
pp. 1944-1964 ◽  
Author(s):  
Mi Yang ◽  
Qi Guo ◽  
Hui Peng ◽  
Yu-Zhong Xiao ◽  
Ye Xiao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Bone Mass ◽  
Noncoding Rna ◽  
Natural Compound ◽  
Novel Mutation ◽  
Gene Mutations ◽  
High Bone Mass ◽  
High Bone ◽  
Chinese Subjects

High bone mass (HBM) is usually caused by gene mutations, and its mechanism remains unclear. In the present study, we identified a novel mutation in the long noncoding RNA Reg1cp that is associated with HBM. Subsequent analysis in 1,465 Chinese subjects revealed that heterozygous Reg1cp individuals had higher bone density compared with subjects with WT Reg1cp. Mutant Reg1cp increased the formation of the CD31hiEmcnhi endothelium in the bone marrow, which stimulated angiogenesis during osteogenesis. Mechanistically, mutant Reg1cp directly binds to Krüppel-like factor 3 (KLF3) to inhibit its activity. Mice depleted of Klf3 in endothelial cells showed a high abundance of CD31hiEmcnhi vessels and increased bone mass. Notably, we identified a natural compound, Ophiopogonin D, which functions as a KLF3 inhibitor. Administration of Ophiopogonin D increased the abundance of CD31hiEmcnhi vessels and bone formation. Our findings revealed a specific mutation in lncRNA Reg1cp that is involved in the pathogenesis of HBM and provides a new target to treat osteoporosis.

scholarly journals Diagnostic deep‐targeted next‐generation sequencing assessment of TP53 gene mutations in multiple myeloma from the whole bone marrow

2020 ◽  
Vol 189 (4) ◽  
Author(s):  
Anna Petrackova ◽  
Jiri Minarik ◽  
Lenka Sedlarikova ◽  
Tereza Libigerova ◽  
Alzbeta Hamplova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Next Generation Sequencing ◽  
Gene Mutations ◽  
Tp53 Gene ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing ◽  
Tp53 Gene Mutations

scholarly journals Effect of Chemical Protection and Bone Marrow Treatment on Radiation Injury in Mice

Blood ◽  
1958 ◽  
Vol 13 (7) ◽  
pp. 665-676 ◽  
Author(s):  
PAUL URSO ◽  
C. C. CONGDON ◽  
D. G. DOHERTY ◽  
RAYMOND SHAPIRA
Keyword(s):  
Bone Marrow ◽  
Body Weight ◽  
Radiation Injury ◽  
Combined Treatment ◽  
X Rays ◽  
Peripheral Blood Leukocytes ◽  
Blood Leukocytes ◽  
Hematopoietic Organs ◽  
X Irradiation ◽  
Bone Marrow Granulocytes

Abstract MEG (prepared from 9.0 mg. of AET) significantly modified the response of the bone marrow, peripheral blood leukocytes, spleen, thymus, body weight, hematocrit, and histology of the hematopoietic organs to lethal (900 r) and sublethal (450 r) x-irradiation in CAF1 mice. MEG reduced the effect of 900 r on the bone marrow, granulocytes of the blood, hematocrit, spleen, thymus, and body weight by a factor of approximately two. Combined treatment (MEG and isologous bone marrow) of mice exposed to 900 r of x-rays demonstrated that MEG is primarily responsible for preventing the early destruction of the bone marrow, but bone marrow injection was primarily responsible for causing a more rapid recovery of the bone marrow. In mice receiving combined treatment, recovery of the leukocytes and spleen was primarily influenced by the bone marrow injection; whereas recovery of the thymus and body weight was primarily influenced by MEG. The hematocrit values were normal after combined treatment.

Detection of Nucleophosmin Gene Mutations in Plasma from Patients with Acute Myeloid Leukemia: Clinical Significance and Implications.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2855-2855
Author(s):  
Wanlong Ma ◽  
Xi Zhang ◽  
Iman Jilani ◽  
Farhad Ravandi ◽  
Elihu Estey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Leukemic Cells ◽  
Striking Difference ◽  
Plasma Dna ◽  
Npm1 Mutation ◽  
Acute Myeloid

Abstract Nucleotides insertion in the nucleophosphamin (NPM1) gene has been reported in about one third of patients with acute myeloid leukemia (AML). Multiple studies showed that the presence of NPM1 mutations associated with better outcome in patients with AML. Studies reported to date have analyzed leukemic cells obtained from bone marrow or peripheral blood. We tested for mutations in the NPM1 gene using peripheral blood plasma and compared results with clinical outcome from a single institution. Analyzing plasma from 98 newly diagnosed patient with AML showed NPM1 mutation in 24 (23%) of patient while only one (4%) of 28 previously untreated patients with myelodysplastic syndrome (MDS) showed NPM1 mutation. Compared with peripheral blood cells, 2 (8%) of the 24 positive patients were negative by cells; none were positive by cells and negative by plasma. Most of the mutations detected (45%) were in patients with FAB classification M2, M4 and M5. In addition to the reported 4 bp insertion, we also detected 4 bp deletion in one patient in cells and plasma. Patients with NPM1 mutation had a significantly higher white blood cell count (P = 0.0009) and a higher blast count in peripheral blood (P = 0.002) and in bone marrow (P = 0.002). Blasts in patients with NPM1 mutant expressed lower levels of HLA-DR (P = 0.005), CD13 (P = 0.02) and CD34 (P < 0.0001), but higher CD33 levels (P = 0.0004). Patients with NPM1 mutation appear to have better chance of responding to standard therapy (P = 0.06). Event free survival of patients with NPM1 mutation was longer (P = 0.056) than in patients with intermediate cytogenetic abnormalities. The most striking difference in survival was in patients who required >35 days to respond to therapy (Figure). Survival was significantly longer in patients with NPM1 mutation requiring >35 days to respond (P = 0.027). This data not only support that NPM1 plays a significant role in the biology and clinical behavior of AML, but also show that plasma DNA is enriched with leukemia-specific DNA and is a reliable source for testing. Figure Figure

Homozygous and Compound Heterozygous Mutations in the Telomerase Reverse Transcriptase Gene in Two Families with Spontaneous Dyskeratosis Congenita and Idiopathic Aplastic Anemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1675-1675
Author(s):  
Hong-Yan Du ◽  
Elena Pumbo ◽  
Peter Manley ◽  
David B. Wilson ◽  
Philip Mason ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Autosomal Recessive ◽  
Amino Acid Change ◽  
Autosomal Dominant ◽  
Bone Marrow Failure ◽  
Gene Mutations ◽  
Dyskeratosis Congenita ◽  
Compound Heterozygous ◽  
The Family ◽  
Tert Gene

Abstract Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome. Classically, DC presents with progressive bone marrow failure, abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia. The pattern of inheritance in families with DC suggests an X-linked recessive, an autosomal dominant, and an autosomal recessive form of DC. However, in the majority of patients the occurrence of the disease is sporadic or the family history is unknown. Mutations in four different genes have been associated with DC so far. Mutations in DKC1 have been shown to account for the X-linked form of DC and DKC1 de novo mutations account for about one third of male patients with sporadic disease. Mutations in the telomerase RNA TERC and in the catalytic subunit of telomerase, TERT, have been shown to be responsible for the autosomal dominant form of DC. Interestingly, patients with heterozygous mutations in TERC and TERT often show a milder form of disease and a later age of onset and often lack the classic mucocutaeous features, thus are classified as atypical DC. Very recently homozygosity for a mutation in NOP10 has been identified in one family with autosomal recessive disease. The products of the genes mutated in DC are all components of the telomerase complex, suggesting that disease in patients with DC is caused by a defect in telomere maintenance. Here we investigated two patients, one UPN # 199.001 presenting with the classic manifestations of DC and the other UPN# 284.001 presenting with progressive bone marrow failure but no other clinical features suggestive of DC. In both patients the telomeres measured in peripheral blood mononuclear cells were very short, being defined as being below the 1st percentile. Mutation analysis in the genes associated with DC revealed that patient 199.001 was homozygous for a novel TERT (C2110T) gene mutation, causing an amino acid change (P704S) within the RT domain of TERT. Both parents were heterozygous for the C to T transition. Interestingly however, the father was in addition heterozygote for a second mutation in TERT (C1234T; H412Y) a mutation which has previously been described and has been shown to reduce telomerase activity by 50%. Investigations of the family revealed that the parent’s were distantly related, explaining the same TERT sequence alteration in both parents. Both arms of the family contained members with pulmonary fibrosis. In the second patient 284.001 we identified two different novel TERT gene mutations. One A2537G causes the amino acid change Y846C in the RT domain of TERT whereas the other C2628G causes H876Q also in the RT domain. One of the mutations was inherited from each parent and the parent with the A2537G mutation also had very short telomeres. These two families illustrate that the pattern of inheritance in patients with DC may be complex and show for the first time that homozygous or compound heterozygous TERT gene mutation may be associated with DC. Co-dominance of the three different TERT gene mutations and the inheritance of short telomeres have possibly contributed to development of disease in these patients who were thought to have sporadic DC and idiopathic aplastic anemia.

Epidemiological and Genetic Analysis of Sideroblastic Anemia — Multicenter Study In Japan

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4225-4225
Author(s):  
Rie Ohba ◽  
Kazumichi Furuyama ◽  
Shigeru Tsuchiya ◽  
Atsushi Manabe ◽  
Etsuro Ito ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Genetic Analysis ◽  
Conflicts Of Interest ◽  
Age Of Onset ◽  
Gene Mutations ◽  
Clinical Information ◽  
Refractory Anemia ◽  
Sideroblastic Anemia ◽  
Ring Sideroblasts ◽  
Amino Acid Mutations

Abstract Abstract 4225 Introduction: Sideroblastic anemia is characterized by anemia with the emergence of ring sideroblasts in the bone marrow. There are two forms of sideroblastic anemia. One is an inherited sideroblastic anemia, and another is an acquired sideroblastic anemia. Because sideroblastic anemia is a rare disease, there are few comprehensive studies of sideroblastic anemia, including clinical and genetic information. In the present study, we have performed national-wide survey of sideroblastic anemia in Japan to investigate the epidemiology and pathogenesis of the disease. Method: This study consists of three-step surveys. First, the patients of sideroblastic anemia were searched by simple questionnaire to hematological department of hospitals in all areas in Japan (first investigation). Next, detailed clinical information of sideroblastic anemia patients were collected (second investigation). Survey items were age of onset, gender, family history, hematology, bone marrow and biochemical findings. Then, genetic analyses of patients who were suspected inherited sideroblastic anemia were performed (third investigation). For the genetic analysis, mutations of ALAS2, ABC7, GLRX5, SLC25A38, which are known to be responsible genes for inherited sideroblastic anemia, were examined. Result: At the first investigation, sideroblastic anemia patients were surveyed in the 1086 institutions of Japan. There were 14 cases of confirmed or suspected cases of inherited sideroblastic anemia and 285 cases of suspected or confirmed cases of acquired sideroblastic anemia. These patients were subjects of second investigation. As of August 9, data of 99 patients have been collected. In these cases there are 7 cases of confirmed inherited sideroblastic anemia, 7 cases of suspected inherited sideroblastic anemia, 28 cases of refractory anemia with ring sideroblasts (MDS-RARS) and 57 cases of refractory cytopenia with multilineage dysplasia with ring sideroblasts (MDS-RCMD-RS). Median age of onset was 70.5 years old in MDS-RCMD-RS cases, whereas that of cases in inherited sideroblastic anemia was 14 years old. Hemoglobin level in inherited sideroblastic anemia and RCMD-RS was 6.7g/dl and 8.3g/dl. MCV was 64.7 fl, 105.1 fl in inherited sideroblastic anemia and RCMD-RS. There was thus significant different between MCV level in inherited sideroblastic anemia and RCMD-RS. Chromosomal abnormality of +8 and idic (X) (q13), associated with ABC7 gene, were detected in 7 and 2 of 25 RCMD-RS patients, respectively. At the moment, 4 confirmed and 4 suspected patients of inherited sideroblastic anemia proceeded to third investigation. As a result, mutations of ALAS2, which is the first enzyme of heme biosynthesis in erythroid cells, have been identified in 6 out of 8 patients. The amino acid mutations were detected in exon 5 (R170C, R170L), exon 9 (R411C, R452C), and exon 11 (V562A). For patients without mutations in ALAS2 gene, mutations of other genes related to inherited sideroblastic anemia have been analyzed; however, no mutations are identified so far. Conclusion: The results showed that RCMD-RS is most common in sideroblastic anemia, and XLSA is most frequent type of inherited sideroblastic anemia. However, there are significant number of suspected cases of inherited sideroblastic anemia. The genetic analysis of these cases, including RARS without chromosomal anomaly, is currently in progress. This research has been supported by Grant-in-Aid for Scientific Research from Ministry of Health, Labour and Welfare of Japan. Disclosures: No relevant conflicts of interest to declare.

Clinical significance of HFE gene mutations in patients with refractory anemia with ring sideroblasts (RARS).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18556-e18556
Author(s):  
Rama Nanah ◽  
Mrinal Patnaik ◽  
Naseema Gangat ◽  
Darci Zblewski ◽  
Rong He ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hereditary Hemochromatosis ◽  
Gene Mutations ◽  
Refractory Anemia ◽  
Heterozygous Mutation ◽  
Hfe Gene ◽  
C282y Mutation ◽  
H63d Mutation ◽  
Ring Sideroblasts ◽  
Hfe Gene Mutations

e18556 Background: RARS is a subtype of myelodysplastic syndromes (MDS) defined by < 5% blasts and ≥15% ring sideroblasts (WHO 2008). Hereditary hemochromatosis is a disorder characterized by dysregulations in iron absorption, largely associated with C282Y and H63D mutations of the HFE gene. Iron levels are elevated in both disorders and pathophysiologic correlations were suggested. HFE gene mutations were previously found higher in MDS compared to controls (50% vs 36%) ( Nearman et al, Am J Hematol 2007). Methods: A total of 168 RARS patients’ data from 1994 to 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our center. We searched patients’ records retrospectively to Identify those tested for HFE gene (C282Y, H62D, S65C) mutations, done inside or outside our institution. Survival estimates were calculated using Kaplan-Meier curves. Results: Out of the 168 RARS patients, only 17 (10%) were tested for HFE gene mutations. Out of the 17 tested, 11 (65%) were found to have mutations; 2 of which (18%) had homozygous H63D mutation, 1 patient (9%) had double heterozygous H63D and C282Y mutations, 5 (45%) had only one H36D heterozygous mutation vs 3 patients (27%) with only one C282Y heterozygous mutation. Only one patient was tested for the additional S65C mutation and it was not detected. H63D mutation was present in a total of 8 patients (73%) vs C282Y mutation which was present in 4 patients (36%). Bone marrow iron stores were increased in all 17 tested patients, except one who had decreased stores, this patient had one heterozygous C282Y mutation. Median overall survival (mOS) was 117 months in the HFE mutated patients vs 75 months in the non-mutated (p = 0.6). Conclusions: Our study found the HFE gene, when tested, to be mutated in higher frequencies among patients with RARS compared to that reported in the general population (65% vs 36%), with H63D mutation in almost three quarters of all mutated patients. Although it did not reach statistical significance, the longer survival observed among HFE mutated patients compared to the wild-type raises the question whether testing for HFE gene mutations among patients with MDS-RARS should be further explored.

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