Epigenomics ; Hematologic Diseases ; genetics ; Humans

Epigenesis, Genetic ; Humans ; Myelodysplastic Syndromes ; genetics

Hematologic Diseases ; diagnosis ; Hematologic Tests ; Humans

Adolescent ; Adult ; Aged ; Case-Control Studies ; Central Nervous System Neoplasms ; cerebrospinal fluid ; diagnosis ; Child ; Female ; Humans ; Hyaluronan Receptors ; cerebrospinal fluid ; Leukemia ; cerebrospinal fluid ; Male ; Middle Aged ; Young Adult

TNF-related apoptosis-inducing ligand (TRAIL) is a newly identified member of the tumor necrosis factor (TNF) family. TRAIL induces apoptosis by activating caspase cascades, stimulating a loss of mitochondrial membrane potential (Delta Psim) and cytochrome C release in the FADD/caspase-8 dependent pathway. However, TRAIL can also trigger transcriptional activations of the pro-oncogene of c-fos, JNK, and NF-kappaB by other signaling pathways downstream of FADD/caspase-8. MAPK/ERK activation has a dominant protecting effect over apoptotic signaling from the death receptors. The functional expression of TRAIL by leukemic cells may be involved in tumor cells evasion of immunosurveillance. Somatic mutations of TRAIL-R1 and TRAIL-R2 genes may play a role in the pathogenesis of some tumors. TRAIL can induce apoptosis on various continuous transformed cell lines and primary tumor cells, including several of hematopoietic origin, displaying minimal toxic effects on normal tissues. Because of the abilities of induction of both cytotoxic (apoptosis) and cytostatic (cell cycle perturbation) effects on the leukemic cells, TRAIL is currently considered as a potential(co) therapeutic drug against tumors.
Animals ; Apoptosis Regulatory Proteins ; Hematologic Neoplasms ; etiology ; therapy ; Humans ; Membrane Glycoproteins ; physiology ; Mutation ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; Receptors, Tumor Necrosis Factor ; genetics ; physiology ; Signal Transduction ; TNF-Related Apoptosis-Inducing Ligand ; Tumor Necrosis Factor-alpha ; physiology

To study the telomerase activity in the bone marrow MNCs from patients with myelodysplastic syndromes in comparison with that in normal individuals and acute leukemia patients. The intracellular telomerase activity was semi-quantitatively examined by PCR-ELISA assay in the marrow cells of 20 normal individuals, 21 cases of myelodysplastic syndromes (MDS) and 32 cases of acute leukemia. Telomerase activity in normal marrow cells was 0 - 0.30 U, with a mean level of (0.11 +/- 0.08) U, in which 3 cases were considered positive according to the standard set by the Kit. In 32 acute leukemia patients, the mean level of telomerase activity was (0.42 +/- 0.26) U (ranged 0 - 0.96 U) with a positive rate of 78.1%, showing a significantly higher activity in acute leukemia (P < 0.01). Moderate telomerase activity was detected in 21 cases of MDS, with a mean level of (0.27 +/- 0.19) U (0 - 0.97 U) from which the positive rate was 66.7%. This value was significantly higher than that in the normal BM (P < 0.05). Moreover, a significantly higher telomerase activity was shown in the high-risk group of MDS (P < 0.05). Based on the international scoring system evaluating the prognosis of MDS (IPPS), telomerase activity in HIGH subgroup was significantly higher than that in INT-1 and INT-2 subgroup (P < 0.05). The level of telomerase activity was not correlated to the chromosome aberrations. These results show that a borderline telomerase activity could be found in normal bone marrow cells. Telomerase activity was markedly higher in acute leukemia. BM of MDS patients demonstrated a moderate telomerase activity. Higher telomerase activity could be found in high-risk group and correlated with poor prognosis.

WT1 gene encodes a zinc finger transcription factor that regulates transcription of its downstream genes. Some of target genes for WT1 are involved in regulating both cell cycle and cellular proliferation and differentiation. However, WT1 itself is regulated by its upstream genes such as NF-kappaB and GATA-1. Thus there exists a pathway of transcriptional regulation mediated by WT1, which controls development of hematopoietic system. Leukemia results from disrupting the homeostasis among hematopoietic proliferation, differentiation and apoptosis, which is often the consequence of an inappropriate expression of transcription factors and subsequent disruption of the normal gene expression pattern. This article reviews the relationship between the WT1-mediated pathway of transcriptional regulation and leukemia.
Animals ; Carrier Proteins ; genetics ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins ; genetics ; DNA-Binding Proteins ; metabolism ; Erythroid-Specific DNA-Binding Factors ; GATA1 Transcription Factor ; Gene Expression Regulation ; Humans ; Leukemia ; etiology ; genetics ; NF-kappa B ; metabolism ; Nuclear Proteins ; genetics ; Retinoblastoma-Binding Protein 7 ; Transcription Factors ; metabolism ; Transcription, Genetic ; WT1 Proteins ; physiology

OBJECTIVETo identify the distribution and differentiation of ABL kinase domain mutation in the Chinese Han nationality imatinib resistant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL).

METHODSBone marrow or peripheral blood samples of 112 imatinib resistant CML patients and 21 Ph(+)ALL patients were obtained from the first affiliated hospital of Soochow university according to local law. Total RNA was extracted from the mononuclear cells using a TRIzol reagent. ABL kinase domain (KD) mutation was detected by direct sequencing.

RESULTSOf the 112 imatinib resistant CML patients, 54.46%(61 cases) had ABL KD mutation. Twenty-three mutants were identified in 20 amino acid sites and 23.21% (26 cases) ABL KD mutations were in P-loop region. ABL KD mutations were also detected in 71.43% (15 cases) imatinib resistant Ph(+)ALL patients, with 10 mutations in 8 amino acid sites. The most frequent mutation was T315I (28.57%), followed by E255K/V (19.05%) and Y253F/H (14.29%). The frequency of T315I was much higher in imatinib resistant Ph(+) ALL than that in imatinib resistant CML (P = 0.001). Ph(+)ALL with additional chromosomal aberrations also had a higher rate of ABL KD mutation than that of CML (P = 0.010). Ph(+)ALL gained ABL KD mutation faster than CML (P < 0.010).

CONCLUSIONChinese imatinib resistant CML and Ph(+)ALL patients had different characteristics in ABL KD mutation. The rate of ABL KD mutation in Ph(+)ALL with additional chromosomal aberrations was much higher than that of CML with additional chromosomal aberrations.

Adolescent ; Adult ; Aged ; Asian Continental Ancestry Group ; genetics ; Benzamides ; pharmacology ; Chromosome Aberrations ; Drug Resistance, Neoplasm ; genetics ; Female ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; genetics ; Middle Aged ; Mutation ; Philadelphia Chromosome ; Piperazines ; pharmacology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; Protein-Tyrosine Kinases ; genetics ; Proto-Oncogene Proteins c-abl ; genetics ; Pyrimidines ; pharmacology ; Young Adult

OBJECTIVETo investigate the frequency of JAK2V617F mutation in Chinese patients with chronic myeloproliferative neoplasms (MPN) and to study the relationship between JAK2V617F mutation and clinical characteristics.

METHODSJAK2V617F mutation was screened by allele-specific polymerase chain reaction (AS-PCR).

RESULTSJAK2V617F mutation was detected in 277 of the 412 patients with MPN. The frequency of JAK2V617F mutation was similar among essential thrombocythemia (ET), idiopathic myelofibrosis (IMF) and chronic myeloproliferative disorders-unclassified (MPD-U) (P > 0.05), but it was significantly lower than that in polycythemia vera (PV) (P < 0.05). The presence of JAK2V617F was found to be significantly correlative with advanced age at diagnosis (P < 0.01) and with higher hemoglobin levels and higher leukocyte counts (P < 0.05). Significant difference was found in complication of vascular events between JAK2V617 positive and negative patients (P < 0.05). JAK2V617F positive MPD-U patients were more prone to progress into typical MPN compared with JAK2V617F negative MPD-U patients. The association between abnormal karyotype and JAK2V617F was not found in cytogenetical analysis of 301 patients.

CONCLUSIONThe presence of JAK2V617F in MPD-U is associated with the disease development. There is a correlation between JAK2V617F mutation in MPN and advanced age, higher leukocyte counts, hemoglobin level and vascular events.

Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Female ; Follow-Up Studies ; Hemoglobins ; metabolism ; Humans ; Janus Kinase 2 ; genetics ; Leukocyte Count ; Male ; Middle Aged ; Mutation ; Myeloproliferative Disorders ; blood ; complications ; genetics ; Polycythemia Vera ; blood ; complications ; genetics ; Primary Myelofibrosis ; blood ; complications ; genetics ; Thrombocythemia, Essential ; blood ; complications ; genetics ; Thrombosis ; etiology ; Young Adult

Objective To systematically evaluate the effect of metformin on the prognosis of diabetic patients combined with gynecologic cancer.Methods The database including PubMed,Embase,CNKI and Wangfang,were electronically searched with no language restriction from their inception to March 2017 to collect the studies about the effect of metformin on the prognosis of diabetic patients combined with gynecologic cancer.The references in reviews were also searched.According to the inclusion and exclusion criteria,two reviewers screened the literatures independently,extracted data and assessed methodological quality by the Newcastle-Ottawa scale.The primary end points included overall survival (OS) and progress free survival (PFS).The outcome measures were the pooled hazard ratios (HR) and 9596 confidence intervals (9596 CI).I2 was performed in a heterogeneity assessment.Publication bias was evaluated by using Begg's funnel plot and Egger's test,and the sensitivity analysis was conducted to confirm robustness.The Meta-analysis was performed using STATA 12.0 software.Results Sixteen eligible retrospective cohort studies were included and the score of quality assessment were ranged from 6 to 9.The Meta-analysis showed that metformin could improve the OS of diabetic patients with gynecologic tumors (HR=0.71,95％CI 0.59-0.85,P=0.000).Subgroup analysis revealed that metformin could improve the OS of diabetic patients combined with endometrial cancer (HR=0.70,95％CI 0.54-0.89,P=0.004) and diabetic patients combined with cervical cancer (HR=0.95,95％CI 0.90-1.00,P=0.048).Meanwhile metformin improved the OS (HR=0.56,95％CI 0.38-0.83,P=0.004) and PFS (HR=0.45,95％CI 0.30-0.68,P=0.000) of diabetic patients with ovarian cancer after adjusting for confounders.Conclusions The use of metformin is positive for the prognosis of diabetic patients combined with gynecologic cancer.It may improve the OS of diabetic patients with endometrial cancer and diabetic patients with cervical cancer.In addition,it improves the OS and PFS of diabetic patients with ovarian cancer.