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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(4): 1186-1190, 2024 Aug.
Article in Chinese | MEDLINE | ID: mdl-39192417

ABSTRACT

OBJECTIVE: To observe the genetic variation of SH2B3 in patients with myeloid neoplasms. METHODS: The results of targeted DNA sequencing associated with myeloid neoplasms in the Department of Hematology, Xuanwu Hospital, Capital Medical University from November 2017 to November 2022 were retrospectively analyzed, and the patients with SH2B3 gene mutations were identified. The demographic and clinical data of these patients were collected, and characteristics of SH2B3 gene mutation, co-mutated genes and their correlations with diseases were analyzed. RESULTS: The sequencing results were obtained from 1 005 patients, in which 19 patients were detected with SH2B3 gene mutation, including 18 missense mutations (94.74%), 1 nonsense mutation (5.26%), and 10 patients with co-mutated genes (52.63%). Variant allele frequency (VAF) ranged from 0.03 to 0.66. The highest frequency mutation was p.Ile568Thr (5/19, 26.32%), with an average VAF of 0.49, involving 1 case of MDS/MPN-RS (with SF3B1 mutation), 1 case of MDS-U (with SF3B1 mutation), 1 case of aplastic anemia with PNH clone (with PIGA and KMT2A mutations), 2 cases of MDS-MLD (1 case with SETBP1 mutation). The other mutations included p.Ala567Thr in 2 cases (10.53%), p.Arg566Trp, p.Glu533Lys, p.Met437Arg, p.Arg425Cys, p.Glu314Lys, p.Arg308*, p.Gln294Glu, p.Arg282Gln, p.Arg175Gln, p.Gly86Cys, p.His55Asn and p.Gln54Pro in 1 case each. CONCLUSION: A wide distribution of genetic mutation sites and low recurrence of SH2B3 is observed in myeloid neoplasms, among of them, p.Ile568Thr mutation is detected with a higher incidence and often coexists with characteristic mutations of other diseases.


Subject(s)
Adaptor Proteins, Signal Transducing , Intracellular Signaling Peptides and Proteins , Mutation , Humans , Adaptor Proteins, Signal Transducing/genetics , Retrospective Studies , Intracellular Signaling Peptides and Proteins/genetics , Genetic Variation , Gene Frequency , Mutation, Missense , Myeloproliferative Disorders/genetics , Male , Hematologic Neoplasms/genetics
2.
Clin Ther ; 46(8): 636-643, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39117488

ABSTRACT

PURPOSE: This first-in-human trial aimed to investigate the pharmacokinetics and pharmacodynamics characteristics and safety and tolerability of single ascending doses of subcutaneous polyethylene glycol-erythropoietin (PEG-EPO) in healthy subjects. METHODS: In this phase I, randomized, double-blind, placebo-controlled, dose-escalating trial, subjects were sequentially enrolled into 7 cohorts with 12 subjects in each cohort and randomized in a 5:1 ratio to receive a single dose of 0.2, 0.4, 0.8, 1.6, 2.4, 3.6, or 4.8 µg/kg PEG-EPO or matching placebo. Safety and tolerability including dose-limiting toxicities (DLTs) were assessed. Pharmacokinetics parameters, including Cmax, AUC0-inf, Tmax, and t1/2, and pharmacodynamics parameters, including reticulocyte count and hemoglobin content, were evaluated. FINDINGS: Eighty-four subjects (median age 30.4 years and 77.4% male) were enrolled. No subjects developed DLTs. Any grade treatment-related adverse events occurred in 66.7% of the subjects, but most (92.9%) were mild. No serious adverse events and no death occurred. Forty percent of the subjects receiving PEG-EPO had iron decreased, 27.1% reported ferritin decreased, 25.7% showed unsaturated iron binding capacity increased, and 17.1% had neutrophil count decreased. Cmax exhibited a dose-disproportionate rise from a geometric mean of 525 pg/mL with 0.2 µg/kg PEG-EPO to 23196 pg/mL with 4.8 µg/kg PEG-EPO. The mean t1/2 ranged between 82.4 ± 21.3 h with 0.4 µg/kg PEG-EPO and 160.6 ± 65.7 h with 1.6 µg/kg PEG-EPO. AUC0-inf displayed a largely dose-proportional rise from 226264.5 pg*h/mL with 0.2 µg/kg PEG-EPO to 5206434.0 pg*h/mL with 4.8 µg/kg PEG-EPO. The absolute reticulocyte count increased with escalating doses of PEG-EPO, with the mean maximal change from baseline between 3.2 ± 1.5*10^10/L (Q1,Q3 1.8-3.6*10^10/L) with PEG-EPO 0.2 µg/kg and 9.3 ± 4.0*10^10/L (Q1,Q3 6.2-13.5*10^10/L) with 3.6 µg/kg PEG-EPO. The mean maximal change from baseline in the mean hemoglobin content ranged between 5.9 ± 4.4 g/L (Q1,Q3 3.5,7.0) with 0.2 µg/kg PEG-EPO and 15.4 ± 8.7 g/L (Q1,Q3 10.5,20.0) with 2.4 µg/kg PEG-EPO. IMPLICATIONS: This trial demonstrated that PEG-EPO was safe and tolerable in healthy subjects. The subcutaneous route of administration allows outpatient treatment and the pharmacokinetics characteristics of PEG-EPO support less frequent dosing regimens and effective treatment for chronic kidney disease patients with anemia. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT03657238.


Subject(s)
Dose-Response Relationship, Drug , Erythropoietin , Healthy Volunteers , Polyethylene Glycols , Humans , Male , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/adverse effects , Polyethylene Glycols/pharmacokinetics , Female , Adult , Double-Blind Method , Erythropoietin/pharmacokinetics , Erythropoietin/administration & dosage , Erythropoietin/adverse effects , Young Adult , Hemoglobins/analysis , Middle Aged , Reticulocyte Count , Injections, Subcutaneous , Area Under Curve
3.
Hematology ; 29(1): 2387878, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39140716

ABSTRACT

Objectives: MDS and AML characterized by TP53 variations have a poor prognosis in general. However, specifically, differences in prognosis have also been observed in patients with different TP53 variants and VAFs.Methods: Here, we retrospectively analyzed datasets of patients with MDS, MPN, and AML who underwent targeted DNA sequencing from February 2018 to December 2023, and patients with reportable TP53 variations were screened. Demographic data and clinical data were collected, and the relationship between TP53 alterations and patient prognosis (AML/MDS) was analyzed using the cBioPortal and Kaplan-Meier Plotter databases. The relationship between the VAFs of TP53 variations and prognoses was analyzed using data from the present study.Results: Sixty-two variants of TP53 were identified in 58 patients. We mainly identified single mutations (79.31%, 46/58), followed by double (17.24%, 10/58) and triple (3.45%, 2/58) mutations. The variations were mainly enriched in exon4-exon8 of TP53. Missense (72.58%, 45/62) mutations were the main type of variations, followed by splice-site (9.68%, 6/62), nonsense (9.68%, 6/62), frameshift (6.45%, 4/62), and indel (1.61%, 1/62) mutations. In this study, p.Arg175His and p.Arg273His were high-frequency TP53 mutations, and DNMT3A and TET2 were commonly co-mutated genes in the three types of myeloid neoplasms; However, we reported some new TP53 variants in MPN that have not been found in the public database. Moreover, MDS or AML characterized by altered TP53 had a shorter OS than patients in the unaltered group (P<0.01), low TP53 mRNA levels were associated with shorter OS in patients with AML (P<0.01). Data from our center further found higher VAF (≥10%) associated with shorter OS in patients with MDS (median 2.75 vs. 24 months) (P<0.01).Conclusion: TP53 mutations are mainly enriched in exon4-exon8, are missense and single mutations in myeloid neoplasms, and are associated with poor prognosis of MDS/AML, and higher VAF (≥10%) of TP53 mutations associated with a shorter OS in patients with MDS.


Subject(s)
Mutation , Myelodysplastic Syndromes , Tumor Suppressor Protein p53 , Humans , Tumor Suppressor Protein p53/genetics , Male , Female , Middle Aged , Aged , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/mortality , Retrospective Studies , Prognosis , Adult , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Aged, 80 and over , Clinical Relevance
4.
Biochem Genet ; 2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38568374

ABSTRACT

JAK2-unmutated erythrocytosis or non-polycythemia vera erythrocytosis is a rare condition comprising both acquired and hereditary forms. Although acquired erythrocytosis has been well-studied, hereditary erythrocytosis remains poorly studied. Genetic alterations associated with hereditary erythrocytosis include mutations in erythropoietin receptor and erythropoietin (EPO), altered oxygen affinity mutations, and variants associated with the oxygen-sensing pathway. We established a molecular diagnostic approach based on these genes and retrospectively evaluated. Peripheral blood from 56 erythrocytosis patients, lacking JAK2 mutation, were screened for oxygen-sensing pathway abnormalities. Two novel mutations were identified in the EGLN1 gene: NM_022051.2:c.712G > C (p.Gly238Arg) and NM_022051.2:c.122A > C (p.Tyr41Ser) in two patients separately. Notably, both reported heterozygous mutations were absent in the population database. Predictions using multiple computer software indicated that these two missense mutations were harmful and induced a highly conserved amino acid change in EGLN1. Patients with the two mutations exhibited normal serum EPO levels and high hemoglobin and hematocrit levels. Additionally, three other variants of genes were identified in the oxygen-sensing pathway, including endothelial PAS domain protein 1 (EPAS1) rs184760160(2/56), and EGLN1 rs186996510(2/56), rs555121182(2/56). These variants were categorized as benign or likely benign. Our findings provide a framework for etiological research and highlight the importance of screening for genetic mutations associated with erythrocytosis in clinical practice.

5.
Nat Aging ; 4(4): 510-526, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38632351

ABSTRACT

DNA damage contributes to the aging of hematopoietic stem cells (HSCs), yet the underlying molecular mechanisms are not fully understood. In this study, we identified a heterogeneous functional role of microcephalin (MCPH1) in the nucleus and cytoplasm of mouse HSCs. In the nucleus, MCPH1 maintains genomic stability, whereas in the cytoplasm, it prevents necroptosis by binding with p-RIPK3. Aging triggers MCPH1 translocation from cytosol to nucleus, reducing its cytoplasmic retention and leading to the activation of necroptosis and deterioration of HSC function. Mechanistically, we found that KAT7-mediated lysine acetylation within the NLS motif of MCPH1 in response to DNA damage facilitates its nuclear translocation. Targeted mutation of these lysines inhibits MCPH1 translocation and, consequently, compromises necroptosis. The dysfunction of necroptosis signaling, in turn, improves the function of aged HSCs. In summary, our findings demonstrate that DNA damage-induced redistribution of MCPH1 promotes HSC aging and could have broader implications for aging and aging-related diseases.


Subject(s)
DNA Damage , Necroptosis , Animals , Mice , Aging/genetics , DNA Damage/genetics , Genomic Instability , Hematopoietic Stem Cells/physiology , Translocation, Genetic
6.
Ther Adv Neurol Disord ; 17: 17562864231219151, 2024.
Article in English | MEDLINE | ID: mdl-38288324

ABSTRACT

Background: Due to the rarity of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, the best first-line treatment has not been established, although there are several options in guidelines. The preferred treatments vary according to the preference of the physician and anecdote. Objectives: First, to analyze the efficacy of a new treatment mode in POEMS syndrome that uses the four-cycle treatment as the induction regimen, followed by sequential transplantation as the consolidation regimen for transplantation-eligible patients, or received another two-cycle treatment for transplantation-ineligible patients. Second, to compare the efficacy and safety of regimens with a proteasome inhibitor (bortezomib-cyclophosphamide-dexamethasone, BCD) or without a proteasome inhibitor (cyclophosphamide-dexamethasone ± thalidomide, CD ± T). Design: We conducted a retrospective study using real-world data from Capital Medical University, Xuanwu Hospital. Methods: A total of 34 newly diagnosed POEMS syndrome patients met Dispenzieri's diagnostic criteria, and those who completed at least four cycles of treatment from July 2013 to March 2021 were included. Results: The overall vascular endothelial growth factor (VEGF) response rate of this new treatment mode was 100%. The cumulative VEGF complete remission (CRV) rate was 67.9%, and the cumulative complete hematological response (CRH) rate was 55.6%. During the median 49-month follow-up, the 5-year-overall survival (OS) rate was 90.7%, the 3-year-progression-free survival (PFS) rate was 78.4%, and the 5-year-PFS rate was 73.8%. The BCD regimen achieved a 75% CRV rate (median time from diagnosis to CRV = 130 days) and 66.7% CRH rate (median time from diagnosis to CRH = 218 days). In addition, the VEGF response was less than the partial remission (PRV) after four-cycle induction treatment, which, together with a decrease on the Overall Neurological Limitation Scale of less than three points 1 year after consolidation treatment, was an independent poor prognostic factor. Conclusion: Bortezomib was well-tolerated by patients with POEMS syndrome. Compared with CD ± T regimen, BCD as the induction regimen achieved better VEGF response and earlier hematological remission. Autologous stem cell transplantation used as consolidation therapy further improved the neurological and hematological remission rates, resulting in better OS and PFS.

7.
Nat Aging ; 4(2): 213-230, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38233630

ABSTRACT

Aged hematopoietic stem cells (HSCs) exhibit compromised reconstitution capacity and differentiation bias toward myeloid lineages. However, the molecular mechanism behind HSC aging remains largely unknown. In this study, we observed that RNA N1-methyladenosine-generating methyltransferase TRMT6-TRMT61A complex is increased in aged murine HSCs due to aging-declined CRL4DCAF1-mediated ubiquitination degradation signaling. Unexpectedly, no difference of tRNA N1-methyladenosine methylome is observed between young and aged hematopoietic stem and progenitor cells, suggesting a noncanonical role of the TRMT6-TRMT61A complex in the HSC aging process. Further investigation revealed that enforced TRMT6-TRMT61A impairs HSCs through 3'-tiRNA-Leu-CAG and subsequent RIPK1-RIPK3-MLKL-mediated necroptosis cascade. Deficiency of necroptosis ameliorates the self-renewal capacity of HSCs and counters the physiologically deleterious effect of enforced TRMT6-TRMT61A on HSCs. Together, our work uncovers a nonclassical role for the TRMT6-TRMT61A complex in HSC aging and highlights a therapeutic target.


Subject(s)
Hematopoietic Stem Cells , Signal Transduction , Mice , Animals , Cell Differentiation/genetics , Aging/genetics
8.
Eur J Haematol ; 111(3): 407-413, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37271577

ABSTRACT

AIMS: To compare cyclosporine (CSA) combining eltrombopag (EPAG) with or without antithymocyte globulin (ATG) in aplastic anemia (AA) patients in the real world. METHODS: AA patients who received ATG combining CSA and EPAG (Group A) and CSA + EPAG (Group B) as front-line treatment in 13 medical centers in China were enrolled. The efficacy and safety were compared. RESULTS: A total of 89 patients were enrolled with 51 patients in Group A and 38 patients in Group B. The 6-month overall response (OR)/complete response (CR) was 73.3%/24.4% and 60.6%/27.3% in Groups A and B (p > .1). For severe AA patients, the 6-month OR was 74.1% versus 50% and 6-month CR was 25.9% versus 20% in Groups A and B (p > 0.1). Multivariate analysis showed gender affects the 6-month OR with females better OR (p = .017, OR 6.045, 95% CI: 1.377-26.546) and time from disease onset to treatment affected the 12-month CR (p = .026, OR 0.263, 95% CI: 0.081-0.852). No difference was found in side effects except ATG infusion reaction and serum sickness. Mortality was 7.8% in Group A and no patient died in Group B. CONCLUSIONS: CSA + EPAG had a similar response and less side effects compared with standard immunosuppressive therapy + EPAG in newly diagnosed AA.


Subject(s)
Anemia, Aplastic , Cyclosporine , Female , Humans , Cyclosporine/adverse effects , Antilymphocyte Serum/adverse effects , Anemia, Aplastic/diagnosis , Anemia, Aplastic/drug therapy , Retrospective Studies , Immunosuppressive Agents/adverse effects , Treatment Outcome
9.
Front Oncol ; 13: 1028571, 2023.
Article in English | MEDLINE | ID: mdl-37152063

ABSTRACT

Maintenance treatment is a pivotal part in the whole process management of multiple myeloma (MM), which further deepens response and improves survival. However, evidence of maintenance in non-transplant MM patients is inadequate in real-world practice. Here, we retrospectively analyzed the efficacy and survival of 375 non-transplant MM patients from 11 centers between 2010 and 2021 in north China. After a median of seven cycles of front-line regimens, there were 141, 79, and 155 patients receiving lenalidomide maintenance (L-MT), bortezomib maintenance (B-MT), or thalidomide maintenance (T-MT), respectively. Patients on L-MT and B-MT had significantly greater proportions of high-risk cytogenetic abnormalities (HRCAs) detected by fluorescence in situ hybridization (FISH), which was defined as 1q21 gain, 17p deletion, adverse immunoglobulin heavy chain (IgH) translocations. Although the progression-free survival (PFS) and overall survival (OS) were comparable among the three groups, L-MT and B-MT remedied the negative impact of HRCAs on survival (PFS of patients with HRCAs vs. patients without HRCAs: L-MT, 26.9 vs. 39.2 months, p=0.19; B-MT, 20.0 vs. 29.7 months, p=0.36; OS not reached in all groups). Patients with HRCAs in the T-MT group presented inferior clinical outcomes compared to standard-risk patients (PFS, 12.1 vs. 22.8 months, p=0.02, HR=1.8, 95% CI 1.0-3.4; OS, 54.9 months vs. NR, p<0.001, HR=3.2, 95% CI 1.5-7.0). Achieving complete response (CR) after induction therapy led to superior PFS compared to other degrees of response, regardless of maintenance medication. Furthermore, maintenance duration over 24 months correlated with favorable survival. Due to the large gap of transplant eligibility in China, optimizing maintenance therapy is important for non-transplant MM patients. In this real-world multi-centered study, our findings suggest that clinicians prefer to prescribe lenalidomide or bortezomib as maintenance therapy in high-risk settings, which are superior to thalidomide in non-transplant MM patients. Achievement of CR and maintenance duration over 2 years are positive factors that influence survival.

10.
Anticancer Drugs ; 34(3): 344-350, 2023 03 01.
Article in English | MEDLINE | ID: mdl-36622759

ABSTRACT

This study aimed to examine the effect of venetoclax coupled with azacytidine in treating older adults with relapsed and refractory (R/R) acute myeloid leukemia (AML). The clinical data of 10 senior patients with AML over 65 years old who were treated with venetoclax and azacytidine, including six patients with R/R AML, were retrospectively evaluated. This study comprised seven males and three females with a median age of 71 years. Five patients had at least one relapse, and one patient did not achieve remission after four cycles of azacytidine monotherapy, considering it resistant. AML with myelodysplasia-related changes was found in four cases. One of the 10 patients died early after 1-13 cycles of venetoclax plus azacytidine treatment due to a protracted period of neutropenia and severe lung infection induced by medications. Six of the remaining nine patients, including six R/R patients, achieved a complete remission (CR) or a CR with incomplete hematologic recovery (CRi). After two cycles of therapy, one patient did not react. Neutropenia lasted an average of 10.5 (6-15) days in all patients, with the most severe cases occurring in the second and third weeks of therapy. Three patients who tested positive for the TP53 gene mutation had the following outcomes: One relapsed patient has been in progression-free remission (PFS) for the past 24 months, whereas another has been in full remission but relapsed 2 months later. Another patient experienced complete remission in myelology for 4 months, but the variable allele fraction (VAF) value steadily rose, suggesting that the illness was on the verge of progressing. IDH2 gene alterations were found in three of four patients who obtained maintained CR for more than 18 months following recurrence. Venetoclax in combination with azacytidine is a successful and well-tolerated therapy for R/R AML in the elderly. Venetoclax and azacytidine may help patients with TP53 mutations and reduce VAF. The IDH2 mutation might be a good predictor of veneclax sensitivity. A notable adverse response in the treatment phase of the regimen is severe infection induced by neutropenia.


Subject(s)
Leukemia, Myeloid, Acute , Neutropenia , Male , Female , Humans , Aged , Azacitidine/adverse effects , Retrospective Studies , Leukemia, Myeloid, Acute/drug therapy , Bridged Bicyclo Compounds, Heterocyclic , Neutropenia/chemically induced , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
11.
Heliyon ; 8(12): e12201, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36578403

ABSTRACT

POEMS syndrome is a plasma cell disease. Clinical manifestations and clinical onset are variable. In recent years, more and more cases of POEMS syndrome with cerebrovascular disease and ischemic stroke have been reported. However, it is rare for patients with POEMS syndrome to present with a cerebrovascular accident as the first clinical manifestation. We presented three cases of POEMS syndrome with cerebral infarction in different phases of the disease. We then searched the literature for studies involving POEMS syndrome complicated with cerebral infarction. There were 81 cases in total. In nine patients, cerebral infarctions occurred before polyneuropathy. Patients with cerebral infarction before polyneuropathy have better prognosis of POEMS than those with cerebral infarction after polyneuropathy.

12.
Mol Genet Genomic Med ; 10(4): e1893, 2022 04.
Article in English | MEDLINE | ID: mdl-35192745

ABSTRACT

To explore the genetic and clinical features of a rare t(1;12)(q21;p13) in a patient with myelodysplastic syndrome (MDS). A 53-year-old male was diagnosed as high-risk MDS, and died in a short period. A complete cytogenetic analysis of bone marrow by conventional G-banding karyotyping was performed at the time of initial evaluation. On the basis of chromosome karyotype, interphase and metaphase fluorescence in-situ hybridization (FISH) were carried out to further confirm the abnormal karyotypes. Reverse-transcription polymerase chain reaction (RT-PCR) was performed to determine ETV6/ARNT fusion gene status. G-banding revealed karyotype 47, XY, +8, der(12) t(1;12)(q21;p13). FISH with the centromere 8 probe verified the trisomy 8, and the ETV 6 break-apart probe suggested heterozygous loss of ETV6 allele located in short arm of chromosome 12. Subsequently, the painting probe of whole chromosome 12 further confirmed the part break of short arm of chromosome 12, and the 1q21/1p36 probe yielded three signals of 1q21 and two signals of 1p36. The results of FISH were in accordance with the karyotype completely. No ETV6/ARNT fusion gene was detected by PCR. T(1;12)(q21;p13) is a rare abnormal karyotype, and the limited reports cannot supply definite clinical significance. Rapid deterioration of our case suggests this translocation of chromosome might have a poor effect on the survival of MDS.


Subject(s)
Myelodysplastic Syndromes , Translocation, Genetic , Humans , In Situ Hybridization, Fluorescence/methods , Karyotyping , Male , Myelodysplastic Syndromes/genetics , Trisomy
13.
Cureus ; 14(11): e32031, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36600821

ABSTRACT

Retroperitoneal fibrosis (RF) is a rare disease, which can be primary (idiopathic) or secondary. We present the case of a 56-year-old patient with symptomatic RF, in whom, after ineffective treatment with glucocorticoids, immunosuppressants, and non-steroidal anti-inflammatory drugs for one year and a progressive clinical course, a follicular lymphoma in the retroperitoneal space and several lymphoma nodes was identified. We also include a literature review on differential diagnosis through image inspection and case reports of lymphoma mimicking RF.

14.
Cell Death Discov ; 7(1): 297, 2021 Oct 18.
Article in English | MEDLINE | ID: mdl-34663800

ABSTRACT

DNA (cytosine-5)-methyltransferase 3A (DNMT3A) mutations occur in ~20% of de novo acute myeloid leukemia (AML) patients, and >50% of these mutations in AML samples are heterozygous missense alterations within the methyltransferase domain at residue R882. DNMT3A R882 mutations in AML patients promote resistance to anthracycline chemotherapy and drive relapse. In this study, we performed high-throughput screening and identified that oridonin, an ent-kaurene diterpenoid extracted from the Chinese herb Rabdosia rubescens, inhibits DNMT3A R882 mutant leukemic cells at a low-micromolar concentration (IC50 = 2.1 µM) by activating both RIPK1-Caspase-8-Caspase-3-mediated apoptosis and RIPK1-RIPK3-MLKL-mediated necroptosis. The inhibitory effect of oridonin against DNMT3A R882 mutant leukemia cells can also be observed in vivo. Furthermore, oridonin inhibits clonal hematopoiesis of hematopoietic stem cells (HSCs) with Dnmt3a R878H mutation comparing to normal HSCs by inducing apoptosis and necroptosis. Overall, oridonin is a potential and promising drug candidate or lead compound targeting DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia.

15.
Cancer Manag Res ; 13: 6231-6238, 2021.
Article in English | MEDLINE | ID: mdl-34393515

ABSTRACT

PURPOSE: Though mutations of the calreticulin (CALR) gene have been identified in essential thrombocythemia patients, the detailed mechanisms for CALR mutations have not been completely clarified. Our study is aimed at characterizing alteration of protein expression in ET patients with mutated CALRdel52 and further recognizing possible involvement of signaling pathways associated with CALR mutations. PATIENTS AND METHODS: Protein pathway array was performed to analyze the expression levels of proteins involved in various signaling pathways in peripheral blood neutrophils from 18 ET patients with mutated CALRdel52 , 20 ET patients with JAK2V617F mutation and 20 controls. RESULTS: We found 20 proteins differentially expressed in ET patients with mutated CALRdel52 compared with healthy controls. These proteins were associated with molecular mechanisms of cancer in ingenuity pathways analysis (IPA) network. We identified top ten canonical pathways which including apoptotic pathways and cellular cytokine pathways might participate in pathogenesis of ET with mutated CALRdel52 . Additionally, there were 8 proteins found to be dysregulated differently between ET patients with mutated CALRdel52 and those with JAK2V617F mutation. These proteins might be related to the unique signaling pathways activated by CALRdel52 mutation which were different to JAK/STATs pathway by JAK2V617F mutation. CONCLUSION: Our study demonstrated that numerous alterations of signaling proteins and pathways in ET patients with mutated CALRdel52 . These findings could help to gain insights into the pathological mechanisms of ET.

16.
Food Funct ; 12(18): 8760-8773, 2021 Sep 20.
Article in English | MEDLINE | ID: mdl-34369950

ABSTRACT

The potential benefits of insoluble dietary fiber (IDF) in the regulation of lipid metabolism have been reported in large prospective cohort studies although the molecular regulatory mechanism is still unclear. Okara is a by-product obtained during soybean processing for soy milk and soybean curd (tofu), which is rarely utilized and can be a cheap potential dietary fiber (DF) resource. In this study, the structure and physicochemical properties of insoluble dietary fiber (SIDF) extracted from okara were characterized, and the prebiotic effects on fat metabolism were investigated in vivo. The results showed that the main monosaccharides of SIDF (90.50%) identified were galactose, arabinose, xylose, rhamnose and glucose. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), and X-ray diffraction (XRD) analyses suggested that SIDF had a loose and porous structure, polysaccharide functional groups, and a typical crystalline cellulose I structure. In addition, SIDF had ideal oil-adsorption capacity (OAC; 7.95 g g-1) and significantly improved cholesterol adsorption (11.14 mg g-1) at pH 7.0. In vivo, IDF supplementation reduced the serum lipid levels and inhibited hepatic fat accumulation. Additionally, SIDF administration improved hepatic steatosis by stimulating lipolysis via upregulation of PPARα, CYP4a10 and CPT1a. This is the first systematic study on the composition, structure, physicochemical properties, adsorption function and biological effects of SIDF. The above results show that SIDF could be used as an ideal functional ingredient in food processing as well as play a positive role in improving the added value of okara and promoting its comprehensive utilization.


Subject(s)
Dietary Fiber , Dyslipidemias/diet therapy , Fatty Liver/diet therapy , Glycine max , Lipid Metabolism , Prebiotics , Adipose Tissue , Adsorption , Animals , Body Weight , Chemical Phenomena , Cholesterol , Diet, High-Fat , Dietary Fiber/analysis , Lipid Metabolism/genetics , Lipids/blood , Lipolysis , Liver/metabolism , Mice , Mice, Inbred C57BL , Prebiotics/analysis , Signal Transduction , Solubility
17.
BMC Med Genomics ; 14(1): 158, 2021 06 13.
Article in English | MEDLINE | ID: mdl-34120595

ABSTRACT

BACKGROUND: Somatic mutations in Wilms' tumor 1 (WT1) and tet methylcytosine dioxygenase 2 (TET2) genes were separately perceived as contributors to hematopoietic disorders and usually thought to have a mutually exclusive effect in acute myeloid leukemia (AML). However, we found novel WT1 and TET2 variants persistently co-existed in a refractory and recurrent AML patient with t(9;11)(p21.3;q23.3); KMT2A-MLLT3, and were only detectable genetic alteration in early recurrence. Hence, these two novel variants were further investigated in patient's family, and the potential effect on disease progression was evaluated at follow-up. CASE PRESENTATION: A 27-year-old male was diagnosed with AML, having t(9;11)(p21.3;q23.3); KMT2A-MLLT3, accompanied by WT1 (NM_024426.6:exon7:c.1109G>C:p.Arg370Pro) and TET2 (NM_001127208.3:exon11:c.5530G>A:p.Asp1844Asn) variants. After two cycles of induction chemotherapy, complete remission was achieved. A consolidation treatment was then completed. However, the evaluation of the bone marrow revealed that early recurrence, WT1 (p.Arg370Pro) and TET2 (p.Asp1844Asn) variants still detectable, instead of KMT2A-MLLT3. Subsequently, these two variants were proved to be germline variants, which inherited from father and mother respectively. And the patient's elder brother also carried TET2 (p.Asp1844Asn) variant. A sequential allogeneic HLA-matched sible hematopoietic stem cell transplantation (allo-HSCT) was carried out, and the donor is the patient's elder brother, the original two variants of patient were replaced by the donor-derived TET2 (p.Asp1844Asn) variant after allo-HSCT; the patient has remained in complete remission with regular follow-up. CONCLUSIONS: In brief, it is firstly reported that WT1 p.Arg370Pro and TET2 p.Asp1844Asn variants co-existed in a refractory and recurrent AML patient by inheritance. These two variants of the patient were replaced with donor-derived TET2 p.Asp1844Asn after allo-HSCT, and the patient has remained in complete remission with regular follow-up.


Subject(s)
Leukemia, Myeloid, Acute
18.
Int J Hematol ; 113(6): 807-814, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33646527

ABSTRACT

It is unknown whether adding stanozolol to decitabine for maintenance can further improve progression-free survival (PFS) and overall survival (OS) after effective decitabine treatment in patients with high-risk myelodysplastic syndrome (MDS). Patients newly diagnosed with high-risk MDS who achieved at least partial remission after 4 cycles of decitabine (20 mg/m2 days 1-5) were selected. In total, 62 patients (median age 66 years) were enrolled, of whom 21 were treated with stanozolol and decitabine for maintenance, and 41 were treated with decitabine alone. The median number of cycles for maintenance treatment was 6 (2-11) and 5 (2-12) for the stanozolol and control groups, respectively (p > 0.05). PFS in the stanozolol group was significantly longer than in the control group (15.0 vs 9.0 months, hazard ratio [HR] = 0.35, 95%CI: 0.19-0.63, p = 0.0005), whereas OS was not significantly prolonged in the stanozolol group (21.0 vs 15.0 months, HR = 0.73, 95%CI: 0.39-1.37, p = 0.33). The proportion of patients with severe neutropenia during maintenance treatment in the stanozolol group was lower than in the control group (76.2% vs 95.1%, p = 0.039). In conclusion, adding stanozolol to decitabine after effective decitabine treatment can prolong PFS and reduce the severity of neutropenia for patients with high-risk MDS.


Subject(s)
Decitabine/administration & dosage , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/mortality , Stanozolol/administration & dosage , Adult , Aged , Disease-Free Survival , Female , Follow-Up Studies , Humans , Male , Middle Aged , Survival Rate
19.
Stem Cells ; 39(2): 240-252, 2021 02.
Article in English | MEDLINE | ID: mdl-33270949

ABSTRACT

The role of mammalian target of rapamycin and its suppressor sirolimus in the regulation of hematopoietic stem and progenitor cells (HSPCs) is controversial. We show here that sirolimus enhanced regeneration of HSPCs in mice exposed to sublethal total body irradiation (TBI) and other regenerative stressors. Sorted Lin- CD150+ bone marrow cells from sirolimus-treated TBI mice had increased expression of c-Kit and other hematopoietic genes. HSPCs from sirolimus-treated TBI mice were functionally competent when tested by competitive engraftment in vivo. Postradiation regeneration of HSPCs in mice treated with sirolimus was accompanied by decreased γ-H2AX levels detected by flow cytometry and increased expression of DNA repair genes by quantitative polymerase chain reaction. Reduction of cell death and DNA damage post-radiation by sirolimus was associated with enhanced clearance of cellular reactive oxygen species (ROS) in HSPCs. Increased HSPC recovery with sirolimus was also observed in mice injected with hematoxic agents, busulfan and 5-fluorouracil. In contrast, sirolimus showed no effect on HSPCs in normal mice at steady state, but stimulated HSPC expansion in mice carrying the Wv mutation at the c-Kit locus. In human to mouse xenotransplantation, sirolimus enhanced engraftment of irradiated human CD34+ cells. In summary, our results are consistent with sirolimus' acceleration of HSPC recovery in response to hematopoietic stress, associated with reduced DNA damage and ROS. Sirolimus might have clinical application for the treatment and prevention of hematopoietic injury.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/physiology , Immunosuppressive Agents/pharmacology , Sirolimus/pharmacology , Animals , Cell Survival/drug effects , Cell Survival/physiology , Cell Survival/radiation effects , Fluorouracil/toxicity , Hematopoietic Stem Cells/radiation effects , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Stem Cells/drug effects , Stem Cells/physiology , Stem Cells/radiation effects , Whole-Body Irradiation/adverse effects
20.
Curr Probl Cancer ; 45(3): 100672, 2021 06.
Article in English | MEDLINE | ID: mdl-33239229

ABSTRACT

Dural plasmacytoma is a type of multiple myeloma of the central nervous system. Our patient presented with symptoms of headache. Imaging findings suspected glioblastoma, whereas pathological findings revealed mucosa-associated lymphoid tissue lymphoma associating with plasma cell differentiation. Further in-depth studies confirmed a diagnosis of dural plasmacytoma. This case indicates that morphological variations may occur in the extramedullary involvement of CD20-positive multiple myeloma. The multidisciplinary team contributes to the diagnosis of hematological diseases.


Subject(s)
Multiple Myeloma/diagnosis , Plasmacytoma/diagnosis , Antineoplastic Agents/therapeutic use , Diagnosis, Differential , Female , Humans , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Plasmacytoma/pathology
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