Objective: To compare the clinical features between the 2 cohorts developing myelodysplastic syndrome or acute myeIogenous Ieukemia in Philadelphia chromosome-negative cells (Ph(-) MDS/AML) and maintaining disease stable in the patients with Philadelphia chromosome-positive chronic myeloid Ieukemia (Ph(+) CML) who had clonal chromosomal abnormalities in Philadelphia chromosome-negative metaphases (CCA/Ph(-)) during tyrosine kinase inhibtor (TKI) - therapy. Methods: We retrospectively analyzed Ph(+) CML patients who developed CCA/Ph(-) during TKI-therapy from May 2001 to December 2017. Results: Data of CCA/Ph(-) 63 patients, including 7 progressing to Ph(-) MDS/AML and 56 remaining disease stable were collected. Compared with those with stable disease, patients with Ph(-)MDS/AML had lower hemoglobin (P=0.007) and platelet (P=0.006) counts, and higher proportion of peripheral blasts (P<0.001) when the first time CCA/Ph(-) was detected, and more mosonomy 7 abnormality (5/7, 71.4%) when MDS or AML was diagnosed; meanwhile, trisomy 8 (32/56, 57.1%) was more common in those with stable disease. Outcome of the patients with Ph(-) MDS/AML were poor. However, most of those with CCA/Ph(-) and stable disease had optimal response on TKI-therapy. Conclusions: A few patients with Ph(+) CML developed CCA/Ph(-) during TKI-therapy, most of them had stable disease, but very few patients developed Ph(-) MDS/AML with more common occurrence of monosomy 7 or unknown cytopenia. Our data suggested the significance of monitoring of peripheral blood smear, bone marrow morphology and cytogenetic analysis once monosomy 7 or unknown cytopenia occurred.
Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/physiopathology* ; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/physiopathology* ; Philadelphia Chromosome ; Protein-Tyrosine Kinases/antagonists & inhibitors* ; Retrospective Studies

The CCAAT enhancer binding protein α (C/EBP α:p42 and p30),which encoded by CCAAT enhancer binding protein α () gene,plays a pretty crucial role in the regulation of myeloid hematopoiesis.The disorder of CEBPA gene expression is an pivotal mechanism of acute myeloid leukemia (AML). The result of uncontrolled expression of C/EBP α gene is the over-expression of p30 and the incomplete loss of p42, both of which contribute to the occurrence of AML. Restoring the expression ratio of C/EBP α such as over-expression of p42 or blocking the carcinogenic pathway of p30 seems to be important for the treatment of AML caused by such causes. In order to better guide medical decision-making, this article reviews research progress on C/EBPα in the pathogenesis of AML.
CCAAT-Enhancer-Binding Protein-alpha ; metabolism ; Gene Expression Regulation, Neoplastic ; Hematopoiesis ; genetics ; Humans ; Leukemia, Myeloid, Acute ; physiopathology

OBJECTIVETo investigate the expression and possible roles of Wnt inhibitory factor-1 (Wif-1) and β-catenin in the Wnt pathway in childhood acute lymphoblastic leukemia (ALL).

METHODSThe clinical data of 35 children who had newly-diagnosed ALL and achieved complete remission on day 33 of remission induction therapy were retrospectively reviewed. The children before treatment were considered as the incipient group, and those who achieved complete remission on day 33 were considered as the remission group. Fifteen children with non-malignant hematologic diseases were enrolled as the control group. RT-PCR was used to measure the mRNA expression of Wif-1 and β-catenin. ELISA was used to measure the protein expression of Wif-1.

RESULTSCompared with the control and remission groups, the incipient group had significantly lower mRNA and protein expression of Wif-1 and significantly higher mRNA expression of β-catenin (P<0.05). In the incipient and remission groups, high-risk children showed significantly higher mRNA expression of β-catenin and significantly lower mRNA and protein expression of Wif-1 than the medium- and low-risk children (P<0.05). In the incipient and remission group, the children with T-cell acute lymphoblastic leukemia showed significantly higher mRNA expression of β-catenin and significantly lower mRNA and protein expression of Wif-1 compared with those with B-lineage acute lymphoblastic leukemia (P<0.05). In each group, there was a negative correlation between the mRNA expression of Wif-1 and β-catenin (P<0.05).

CONCLUSIONSReduced expression of Wif-1 and increased expression of β-catenin may be involved in the pathogenesis of childhood ALL, and the degree of reduction in Wif-1 and/or increase in β-catenin may be related to prognosis.

Adaptor Proteins, Signal Transducing ; genetics ; physiology ; Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; etiology ; physiopathology ; RNA, Messenger ; analysis ; Repressor Proteins ; genetics ; physiology ; Wnt Signaling Pathway ; physiology ; beta Catenin ; genetics ; physiology

OBJECTIVETo investigate the value of myeloproliferative neoplasms Symptom Assessment Form total symptom score (MPN-SAF-TSS)in assessing constitutional symptoms among Ph/BCR- ABL negative myeloproliferative neoplasm (MPN)patients.

METHODSA cohort of 628 MPN patients were evaluated by MPN- SAF- TSS.

RESULTSFatigue was the most common symptom (76.0%, 76.2%vs 89.9%)and the highest average severity of all the symptoms (3.46±2.97, 3.47±2.99vs 4.74±3.04 scores)among polycythemia vera (PV), essential thrombocythemia (ET)and primary myelofibrosis (PMF)patients. Using the MPN- SAF- TSS analysis, PMF patients showed highest burden of symptoms (28.9 ± 19.1), followed by PV patients (19.2 ± 16.8), and finally ET patients (17.1 ± 15.3). Instinct differences were observed between PMF and PV patients (χ(2)=6.371,P=0.021), PMF and ET patients (χ(2)= 14.020,P<0.001). No significant difference was found between PV and ET patients (χ(2)=2.281,P=0.191).

CONCLUSIONMPN- SAF- TSS was effective in evaluating the symptomatic burden among Ph/BCRABL negative MPN patients and could be used for serial assessment in this clinical setting.

Humans ; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative ; diagnosis ; physiopathology ; Polycythemia Vera ; complications ; Primary Myelofibrosis ; complications ; Thrombocythemia, Essential ; complications

Cryptotanshinone (CPT), a lipid soluble active compound in Salvia miltiorrhiza, has a significant inhibitory effect on multiple malignant tumors, e. g. chronic myeloid leukemia (CML) cells and can effectively enhance imatinib's chemotherapeutic effect. However, its functional molecular mechanism remained unclear. In this experiment, the authors conducted a systematic study on the effect of CPT on the imatinib sensitivity and P-glycoprotein (P-gp) expression in CML cells by using CML cells K562 and imatinib persister K562-R. The MTT assays were performed to determine CPT's impact on the inhibitory effect of imatinib. Annexin V-FITC/PI staining analysis was used to detect the changes in the cell apoptosis rate. The active changes in apoptosis regulatory proteins Caspase-3, Caspase-9 and PARP were determined by Western blot. After the cells were pretreated with the gradient concentration of CPT, the expression of P-gp was analyzed by Western blot and flow cytometry. The changes in intracellular concentrations of imatinib were determined by HPLC analysis. The results indicated that the pretreatment with CPT significantly increased the proliferation inhibiting and apoptosis inducing effects of imatinib on K562 and K562-R cells as well as the degradation product expression of pro-apoptotic proteins Caspase-3, Caspase-9 and PARP, with a significant difference with the control group (P < 0.01). However, CPT showed no impact on the P-gp expression in CML cells and the intracellular concentrations of imatinib. In summary, the findings suggested that CPT enhanced the sensitivity of CML cells to imatinib. Its mechanism is not dependent on the inhibition in P-gp expression and the increase in intracellular drug concentration.
ATP-Binding Cassette, Sub-Family B, Member 1 ; genetics ; metabolism ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Caspase 3 ; genetics ; metabolism ; Caspase 9 ; genetics ; metabolism ; Drug Resistance, Neoplasm ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; Humans ; Imatinib Mesylate ; pharmacology ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; genetics ; metabolism ; physiopathology ; Phenanthrenes ; pharmacology

OBJECTIVETo explore the biological mechanisms underlying Angelica sindsis polysaccharide (ASP) -induced aging of human-derived leukemia stem cells (LSCs) in vitro.

METHODAcute myelogenous leukemia stem cells were isolated by magnetic activated cell sorting (MACS). The ability of LSC proliferation treated by various concentration of ASP(20-80 mg · L(-1)) in vitro for 48 hours were tested using cell counting Kit-8 ( CCK8) , colony forming were evaluated by methylcellulose CFU assay. The ultra structure changes of AML CD34+ CD38- cells were analyzed by transmission electron microscopy. The aging cells were detected with senescence-β-galactosidase Kit staining. Expression of aging-related p53, p21, p16, Rb mRNA and P16, Rb, CDK4 and Cyclin E protein were detected by quantitative reverse transcription polymerase chain reaction( qRT-PCR) and Western blotting, respectively.

RESULTThe purity of the CD34 + CD38 - cells is (91.15 ± 2.41)% after sorted and showed good morphology. The proliferation of LSC was exhibited significantly concentration-dependent inhibited after exposure to various concentration of ASP. Treated by 40 mg · L(-1) ASP for 48 hours, the percentage of positive cells stained by SA-β-Gal was dramatically increased (P < 0.01) and the colony-formed ability has been weakened (P < 0.01). The observation of ultrastructure showed that cell heterochromatin condensation and fragmentation, mitochondrial swelling, lysosomes increased in number. Aging-related p53, p21, p16, Rb and P16, Rb were up-regulated, protein regulatory cell-cycle CDK4 and Cyclin E were down-regulated. ASP may induce the senescence of LSCs effectively in vitro, P16-Rb cell signaling pathway play a significant role in this process.

CONCLUSIONASP can induce human leukemia stem cell senescence in vitro, the mechanism involved may be related to ASP regulation P16-Rb signaling pathways.

Angelica sinensis ; chemistry ; Cell Cycle ; drug effects ; Cell Cycle Proteins ; genetics ; metabolism ; Cells, Cultured ; Cellular Senescence ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; Gene Expression Regulation, Leukemic ; drug effects ; Humans ; Leukemia ; drug therapy ; genetics ; metabolism ; physiopathology ; Neoplastic Stem Cells ; cytology ; drug effects ; Polysaccharides ; pharmacology ; Signal Transduction ; drug effects

During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNA-independent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cell identity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax (TrxG) and Polycomb (PcG) group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cell identity, mammary gland remodeling, and breast cancer initiation.
Animals ; Breast Neoplasms ; genetics ; pathology ; physiopathology ; Cell Transformation, Neoplastic ; Chromatin ; genetics ; metabolism ; Epigenesis, Genetic ; physiology ; Epithelial Cells ; cytology ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Histone-Lysine N-Methyltransferase ; Humans ; Mammary Glands, Animal ; cytology ; growth & development ; Mammary Glands, Human ; cytology ; growth & development ; Myeloid-Lymphoid Leukemia Protein ; genetics ; physiology ; Polycomb-Group Proteins ; genetics ; physiology ; Receptors, Estrogen ; metabolism

The purpose of this review is to provide an overview of the effect of (lymph)angiogenic cytokines on hematopoietic cells involved in acute myeloid leukemia (AML). Like angiogenesis, lymphangiogenesis occurs in pathophysiological conditions but not in healthy adults. AML is closely associated with the vasculature system, and the interplay between lymphangiogenic cytokines maintains leukemic blast survival in the bone marrow (BM). Once AML is induced, proangiogenic cytokines function as angiogenic or lymphangiogenic factors and affect hematopoietic cells, including BM-derived immune cells. Simultaneously, the representative cytokines, VEGFs and their receptors are expressed on AML blasts in vascular and osteoblast niches in both the BM and the peripheral circulation. After exposure to (lymph)angiogenic cytokines in leukemogenesis and infiltration, immune cell phenotypes and functions are affected. These dynamic behaviors in the BM reflect the clinical features of AML. In this review, we note the importance of lymphangiogenic factors and their receptors in hematopoietic cells in AML. Understanding the functional characterization of (lymph)angiogenic factors in the BM niche in AML will also be helpful in interrupting the engraftment of leukemic stem cells and for enhancing immune cell function by modulating the tumor microenvironment.
Animals ; Cytokines/*immunology ; Hematopoietic Stem Cells/immunology/*pathology ; Humans ; Immunity, Cellular ; Leukemia, Myeloid, Acute/immunology/*physiopathology ; *Lymphangiogenesis ; Lymphatic Vessels/immunology/*physiopathology ; Vascular Endothelial Growth Factor A/immunology

The latest findings of our laboratory showed that Angelica sinensis polysaccharide (ASP) showed a definite effect in regulating the aging of hematopoietic stem cells. Leukemia is a type of malignant hematopoietic tumor in hematopoietic stem cells. There have been no relevant reports about ASP's effect in regulating the aging of leukemia cells. In this study, human acute myeloid leukemia (AML) KG1alpha cell lines in logarithmic growth phase were taken as the study object, and were divided into the ASP group, the cytarabine (Ara-C) group, the ASP + Ara-C group and the control group. The groups were respectively treated with different concentration of ASP, Ara-C and ASP + Ara-C for different periods, with the aim to study the effect of ASP combined with Ara-C in regulating the aging of human acute myeloid leukemia KG1alpha cell lines and its relevant mechanism. The results showed that ASP, Ara-C and ASP + Ara-C could obviously inhibit KG1alpha cell proliferation in vitro, block the cells in G0/G1 phase. The cells showed the aging morphological feature. The percentage of positive stained aging cells was dramatically increased, and could significantly up-regulate the expression of aging-related proteins P16 and RB, which were more obvious in the ASP + Ara-C group. In conclusion, the aging mechanism of KG1alpha cell induced by ASP and Ara-C may be related to the regulation of the expression of aging-related proteins, suggesting that the combined administration of ASP and anticancer drugs plays a better role in the treatment of leukemia .
Aging ; drug effects ; genetics ; metabolism ; Angelica sinensis ; chemistry ; Cell Cycle ; drug effects ; Cell Proliferation ; drug effects ; Cyclin-Dependent Kinase Inhibitor p16 ; genetics ; metabolism ; Humans ; Leukemia ; drug therapy ; genetics ; metabolism ; physiopathology ; Polysaccharides ; pharmacology ; Retinoblastoma Protein ; genetics ; metabolism ; Tumor Cells, Cultured

AIM: Ursolic acid (UA), a pentacyclic triterpenoid, is used as an anti-inflammatory and anti-cancer agent. There were few studies on the effects of UA on differentiation, and this is the first time to elucidate the potential effect and molecular mechanism of UA on inducing differentiation in the human leukemia cell line U937. METHODS: Wright-Giemsa staining, nitroblue tetrazolium reduction assay and flow cytometric analysis were utilized to demonstrate the differentiation of U937 cells induced by UA. Western blotting and immunofluorescence assay were used to investigate the possible mechanism. RESULTS: It was found that UA could induce the differentiation of U937cells and Akt-activity was significantly increased during differentiation. Additionally, LY294002, a PI3K-Akt inhibitor, could block the differentiation of U937 cells induced by UA. CONCLUSION UA could induce the differentiation of U937 cells by activating the PI3K/Akt pathway, and it could be a potential candidate as a differentiation-inducing agent for the therapy of leukemia.
Apoptosis ; drug effects ; Cell Proliferation ; drug effects ; Humans ; Leukemia ; enzymology ; genetics ; physiopathology ; Phosphatidylinositol 3-Kinases ; genetics ; metabolism ; Proto-Oncogene Proteins c-akt ; genetics ; metabolism ; Signal Transduction ; drug effects ; Triterpenes ; pharmacology ; U937 Cells