Myelogenous Leukemia Research Articles

Chronic myelogenous leukemia with JAK2 V617F mutation: report of one case and review of literature

目的 探讨伴有JAK2 V617F基因突变的慢性粒细胞白血病（CML）患者的临床特点、发病机制、治疗及预后。 方法 对东莞市人民医院新诊断的1例伴有JAK2 V617F突变的CML患者的临床特征以及予酪氨酸激酶抑制剂（TKI）治疗后的疗效进行观察，并进行相关文献复习。 结果 患者发病时巨脾，白细胞计数（WBC）显著增多，伴有JAK2 V617F突变，但临床分期仍处于慢性期。TKI靶向治疗期间，WBC降至正常，但贫血并未获得显著改善，脾脏虽有缩小，但难以恢复正常。 结论 当CML患者经TKI单药靶向治疗而疗效不佳时，不应单纯考虑疾病进展，而应考虑是否伴随有JAK2 V617F基因突变，并进一步探讨以TKI为基础的联合方案的疗效。

Erratum: BCR-ABL exon 7 deletion and novel point mutation in patient with chronic myelogenous leukemia.

[This corrects the article DOI: 10.1002/ccr3.1794.].

Synthesis, characterization and cytotoxic activity of organoruthenium(II)-halido complexes with 5-chloro-1H-benzimidazole-2-carboxylic acid

Three new ruthenium(II)-arene halido complexes, [(η6-p-cymene) RuX(L)] (1–3), were synthesized in a reaction of [(η6-p-cymene)RuX2]2 with 5-chloro-1H-benzimidazole-2-carboxylic acid (HL) in ethanol (X– = Cl– (1), Br– (2), I– (3)). The complexes were characterized by elemental analysis, mass spectrometry, IR, 1H and 13C NMR spectroscopy. The cytotoxic activity of the ligand precursor and its ruthenium complexes was tested by MTT assay in human cancer cell lines: lung adenocarcinoma (A549), myelogenous leukemia (K562) as well as in one normal human fetal lung fibroblast cell line (MRC-5). The results show that ruthenium(II)-arene complexes possess enhanced cytotoxicity when compared to HL in the range of concentrations up to 300 µM. In terms of halido ligand substitution, cytotoxic activity toward A549 and K562 cell lines in 1–3 serie significantly increased (e.g., IC50 values for K562: 1: 205.76 µM; 2: 174.77 µM; 3: 83.97 µM). All studied compounds were found to be ineffective toward MRC-5. Hydrolysis of 1–3 was followed by UV-vis spectroscopy at 25 °C, revealing ligand-substitution reactions at the Ru(II) center. Compounds 2 and 3 underwent rapid hydrolysis ranging from a few minutes for the aquation to ca. 20 min, confirming typical Ru-arene behavior in aqueous solutions.

Chronic myelogenous leukemia combined with solid malignant neoplasms: report of eight cases and review of literature

Objective To explore the clinical features of chronic myelogenous leukemia (CML) combined with solid malignant neoplasms. Methods The clinical data of 8 CML patients with solid malignant neoplasms who were admitted to the Affiliated Tumor Hospital of Zhengzhou University, the Central Hospital of Nanyang City, the First Affiliated Hospital of Science and Technology University of Henan, and the Central Hospital of Xinxiang City from August 2006 to August 2018 were analyzed retrospectively. The clinical features, treatment and prognosis of the patients were summarized with the review of literature. Results Among the 8 patients, 3 were male and 5 female, aged 40-76 years, with a median of 50 years old. Seven cases were in CML chronic phase, and 1 was in accelerated phase. Seven patients were treated with tyrosine kinase inhibitor (TKI), and only 1 patient was treated with hydroxyurea. In 8 patients, two cases presented with synchronous multiple primary cancer (SMPC), 6 cases presented with heterochrony multiple primary cancer (HMPC). two patients received the operation, 1 patient received the operation and chemotherapy, 4 patients received chemotherapy, and 1 patient received the isotope treatment. One SMPC patient died and another one was under treatment, and 6 HMPC patients were under treatment. Conclusions The relationship between CML and solid malignant neoplasm is under discussion, but patients with CML and solid malignant neoplasm are not unusual. Clinicians should raise awareness to avoid misdiagnosis. The treatment should follow the two main lines that are comprehensive treatment and individualized treatment. Key words: Leukemia, myelogenous, chronic; Neoplasms, multiple primary; Treatment; Prognosis

Progress of immunotherapy of acute myelogenous leukemia

Acute myelogenous leukemia(AML) is a highly heterogeneous malignant hematologic disease, and its clinical treatment mainly includes traditional chemotherapy, but the efficacy is limited and the patients with worse performance status and comorbidities can not be treated with chemotherapy. In recent years, immunotherapy has achieved certain curative effects in AML which shows a promising prospect. This review introduces immunotherapy of AML reported in 60th American Society of Hematology(ASH) Annual Meeting. Key words: Leukemia, myelogenous, acute; Immunotherapy

Clinical analysis of imatinib mesylate in the treatment of chronic myeloid leukemia

Objective To study and explore the clinical effect of imatinib mesylate in the treatment of chronic myeloid leukemia. Methods From January 2013 to January 2017, 60 patients with chronic myeloid leukemia in the Second Hospital of Jiaxing were included in the study.The patients were randomly divided into control group and observation group, with 30 cases in each group.The control group was given routine chemotherapy, the observation group was given routine chemotherapy combined wth imatinib mesylate orally.After 6 months of treatment, the clinical curative effect, the incidence of adverse reactions, immune function, quality of life score of the two groups were compared. Results The response rate of the observation group was 76.67%(23/30), which was higher than 50.00%(15/30) of the control group (χ2=4.593, P 0.05). After treatment, the indicators of immune function in the observation group were higher than those in the control group(t=4.482, 3.731, 3.361, all P<0.05). After treatment, the quality of life scores in the observation group were higher than those in the control group(t=8.898, 5.945, 9.309, 5.679, all P<0.05). Conclusion Imatinib mesylate in the treatment of patients with chronic myelogenous leukemia can effectively improve the efficacy and safety of chemotherapy, reduce the effect of chemotherapy on the immune function of patients, improve their quality of life. Key words: Leukemia, myelogenous, chronic; Inatinib; Immune; Quality of life

Erianin induces cell apoptosis through ERK pathway in human nasopharyngeal carcinoma

BackgroundNasopharyngeal carcinoma (NPC) is one of the most common cancers in areas of Southeast Asia, such as Taiwan, and North Africa. The treatments of NPC, including radiotherapy and chemotherapy, were effective, but they also caused some severe side effects. Erianin, a natural product derived from Dendrobium, was proved to have anti-cancer effect in hepatoma, melanoma, non-small-cell lung carcinoma, myelogenous leukemia, breast cancer, and osteosarcoma. Hypothesis/PurposeAccording to previous research, we hypothesized that erianin inhibits cancer cell growth through apoptotic mechanisms. This study aimed to determine whether Erianin has an anti-NPC effect and what mechanisms were involved. Methods and ResultsThe result showed that erianin significantly increased activation of apoptosis in NPC cell lines (NPC-039 and NPC-BM) and arrest the cell cycle obviously through mitochondrial membrane alternation, death receptors activation, and caspase-3, -8, -9 activation. Phosphorylated ERK1/2 was also decreased in erianin-treated NPC cell with dose-dependent manner, and the result was thought to promote apoptosis. Furthermore, the increased rate of apoptotic cells with erianin plus it’s inhibitors (U) was also revealed in this study. ConclusionIn conclusion, this is the first research to identify the anti-NPC effect of erianin via the apoptosis mechanism. Erianin was a promising natural agent against nasopharyngeal carcinoma.

MicroRNA in leukemia: Tumor suppressors and oncogenes with prognostic potential.

Leukemia is known as a progressive malignant disease, which destroys the blood-forming organs and results in adverse effects on the proliferation and development of leukocytes and their precursors in the blood and bone marrow. There are four main classes of leukemia including acute leukemia, chronic leukemia, myelogenous leukemia, and lymphocytic leukemia. Given that a variety of internal and external factors could be associated with the initiation and progression of different types of leukemia. One of the important factors is epigenetic regulators such as microRNAs (miRNAs) and long noncoding RNAs (ncRNA). MiRNAs are short ncRNAs which act as tumor suppressor (i.e., miR-15, miR-16, let-7, and miR-127) or oncogene (i.e., miR-155, miR-17-92, miR-21, miR-125b, miR-93, miR-143-p3, miR-196b, and miR-223) in leukemia. It has been shown that deregulation of these molecules are associated with the initiation and progression of leukemia. Hence, miRNAs could be used as potential therapeutic candidates in the treatment of patients with leukemia. Moreover, increasing evidence revealed that miRNAs could be used as diagnostic and prognostic biomarkers in monitoring patients in early stages of disease or after received chemotherapy regimen. It seems that identification and development of new miRNAs could pave to the way to the development new therapeutic platforms for patients with leukemia. Here, we summarized various miRNAs as tumor suppressor and oncogene which could be introduced as therapeutic targets in treatment of leukemia.

Expressions of CD34, CD123 and CD38 in acute myelogenous leukemia and their clinical significances

Objective To investigate the expressions of CD34, CD123 and CD38 in acute myelogenous leukemia (AML) and their clinical significances. Methods A total of 164 patients with AML in Xiangya Hospital of Central South University from February 2014 to July 2015 were enrolled. Cellular immunophenotyping was performed by flow cytometry. According to the expressions of CD34, CD38 and CD123, 164 patients were divided into positive group and negative group, and the clinical data and immature cells ratio of two groups were compared. Results In 164 patients with AML, 102 cases (62.2%) were CD34 positive, 126 cases (76.8%) were CD123 positive, and 144 cases (88.3%) were CD38 positive. There were no significant differences in age and sex between the positive and negative groups (P > 0.05). But there were significant differences in the proportion of immature cells, white blood cell count and hemoglobin between the two groups (all P < 0.05). The expression rates of CD34, CD38 and CD123 were correlated with minimal residual disease and complete remission rate (all P < 0.05). Conclusions CD34, CD123 and CD38 are effective markers for AML detection. The expressions of CD34, CD123 and CD38 can be used as the judgment marker of cell maturity, which is conducive to the determination of the condition and prognosis of AML patients. Key words: Leukemia, myelogenous, acute; CD34; CD123; CD38

Correction: CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia.

[This corrects the article DOI: 10.18632/oncotarget.11425.].

Targeting the Process of c-MYC Stabilization in Chronic Myelogenous Leukemia

Targeting the Process of c-MYC Stabilization in Chronic Myelogenous Leukemia

Clinical observation of domestic generic imatinib for newly diagnosed chronic myelogenous leukemia in chronic phase

目的 观察国产甲磺酸伊马替尼治疗初诊慢性粒细胞白血病慢性期（CML-CP）的效果及安全性。 方法 回顾性分析东莞市人民医院2014年10月至2016年10月收治的23例年龄>18岁、初次确诊、除羟基脲外未接受其他任何抗CML治疗的CML-CP患者临床资料，所有患者均接受国产甲磺酸伊马替尼400 mg/次，1次/d口服治疗，评价3、6、12个月时的血液学、分子生物学反应及安全性。 结果 23例患者治疗后均达到血液学完全缓解。在可评估的20例患者中，在3个月时15例bcr-abl国际标准化（IS）值<10%；治疗6个月时16例达bcr-abl<1%；治疗12个月时8例bcr-abl<0.1%。不良反应均可耐受。 结论 国产甲磺酸伊马替尼治疗初诊CML-CP疗效可靠，不良反应可耐受。

Progress of autophagy in treatment of chronic myelogenous leukemia

Autophagy plays an important role in the occurrence, progression and treatment of cancer, neurodegenerative, autoimmune and inflammatory diseases. Recent years, autophagy has become a new hot spot in tumor area. Chronic myelogenous leukemia (CML) is a common hematopoietic malignancy; while autophagy is involved in its development, as well as targeting drug tyrosine kinase inhibitor resistance mechanisms, regulating autophagy provide a new direction for the treatment of CML. The intensive study of the relation between cell autophagy and cancer will help to overcome cancer. This article offers an up-to-date comprehensive review of autophagy and CML. Key words: Leukemia, myelogenous, chronic; Autophagy

Negative regulation of microRNA-9 by ecotropic viral integration site1 involved in the pathogenesis of acute myeloid leukemia

Objective To investigate the regulation mechanism of microRNA-9(miR-9)by ecotropic viral integration site1(EVI1)its impact on proliferation of AML cells and its role in the pathogenesis of myelogenous leukemia. Methods EVI1 was forced to express in Uocm1 cell lines by murine stem cell virus-EVI1(MSCV-EVI1) plasmid infection.EVI1 overexpressed Uocm1 cells were then treated with 0.1 μmol/L 5-aza-2′-deoxycytidine (5-AZA) dissolved in dimethyl sulfoxide (DMSO). The methylation level of miR-9 promoter was tested by DNA bisulfite sequencing technology.The cell cycle was observed by flow cytometry (FCM). The proliferation ability of the cells was detected by the colony forming assay in semi-solid Methylcellulose medium culture. Results EVI1 level was dramatically increased after being infected by MSCV-EVI1 plasmid.Forced expression of EVI1 in Uocm1 significantly downregulated miR-9 by inducing hypermethylation of miR-9 promoter.Relative expression level of miR-9 was lower in EVI1 overexpressed group(0.004±0.000)than that of the control group(0.006±0.001)(t=4.09, P<0.05). When EVI1 was overexpressed in Uocm1, the rate of G0/G1 cells decreased markedly(P<0.05), while rates of S phage and G2 phage increased significantly(all P<0.05). Seven days after 500 cells plated in semi-solid medium, EVI1 overexpressed Uocm1 cells gave rise to more colony (122.3±7.8) than Uocm1 cells infected with vector(45.7±6.1)(t=-13.44, P<0.01).0.1 μmol/L 5-AZA recovered miR-9 expression(P<0.01)by decreasing EVI1 induced hypermethylation of miR-9 promoter.G0/G1 phase cell proportion was(48.25±2.19)% in control group, while (65.90±2.90)% in 5-AZA group(t=-6.85, P<0.05).5-AZA group formed less colony (51.00±10.01)than the control group (123.40±8.12) (t=9.59, P<0.01), which indicated that 5-AZA inhibited cell proliferation by G0/G1 cell cycle retardation in EVI1 overexpressed uocm1 cells. Conclusions EVI1 may enhance proliferation ability of myeloid leukemia cells by downregulating miR-9 through inducing hypermethylation of miR-9 promotor, which plays a crucial role in the pathogenesis of AML.5-AZA may be an effective hypomethylating agent in the therapy of EVI1 high acute myeloid leukemia. Key words: Ecotropic viral integration site 1; MicroRNA-9; Acute myeloid leukemia; Pathogenesis; 5-aza-2′-deoxycytidine

Long noncoding RNA UCA1 promotes cell proliferation, migration and invasion of human leukemia cells via sponging miR-126.

Acute myeloid leukemia (AML) is a bone marrow malignancy. Long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) plays an important role in several cancers. However, the role of lncRNA UCA1 in AML remained unclear. LncRNA UCA1 expressions in different cell lines were determined by RT-PCR. In human myelogenous leukemia (ML) cell lines K562 and HL60, effects of lncRNA UCA1 knockdown on cell viability, migration, invasion, and apoptosis were assessed, respectively. Binding effects between lncRNA UCA1 and microRNA (miR)-126, and between miR-126 and RAC1 3'UTR were detected by RT-PCR and luciferase activity assay. Involvements of miR-126 and RAC1 in lncRNA UCA1-mediated cell bioactivities were assessed. We found that lncRNA UCA1 was upregulated in ML cell lines. Knockdown of lncRNA UCA1 inhibited cell viability, migration, invasion, and prompted apoptosis of ML cells in vitro. LncRNA UCA1 could bind with miR-126 and downregulate miR-126 expression. Simultaneously, the anti-growth and anti-metastasis actions of lncRNA UCA1 knockdown on ML cells were reversed by miR-126 suppression. RAC1 was a target gene of miR-126, and the anti-ML actions of miR-126 were abolished by RAC1 overexpression. Moreover, PI3K/AKT and JAK/STAT signaling pathways were blocked by miR-126 overexpression while were activated by RAC1 overexpression. Taken together, this study elucidates a novel UCA1-miR-126-RAC1 regulatory network in ML cells, which may provide the feasibility for use lncRNA-based therapy in AML treatment.

Expression of CD47 in de novo acute myelogenous leukemia with normal karyotype and its clinical significance

Objective To investigate the CD47 expression in de novo acute myelogenous leukemia (AML) patients with normal karyotype and its clinical significance. Methods One hundred thirty-seven cases of de novo AML with normal karyotype and 3 healthy volunteers were selected. Relative CD47 expressions in normal bone marrow hematopoietic stem cells (HSC) and multipotent progenitor (MPP) from healthy volunteers, as well as bone marrow mononuclear cells (MNC) and leukemia stem cells (LSC, Lin- CD34+ CD38- CD90-) from AML patients were determined by flow cytometry. CD47 expression on the Lin- CD34+ CD38- LSC-enriched fraction of specimen was determined by flow cytometry. The FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) was detected by using the Genome Analyzer platform. CD34+ CD38- CD47hi and CD34+ CD38- CD47lo expressing cells were identified and purified using FACS. Two groups of cells were inoculated with MethoCult H4445 medium on agarose-containing methylcellulose plates. After 12 days, MPP colony forming units (CFU) were counted, and 1×105 CD34+ CD38- CD47lo and CD34+ CD38- CD47hi cells were transplanted into NSG (NOD-SCID IL-2R γ null) mice irradiated by 280 cGy, and mice were sacrificed after 8 weeks. The ratio of human CD45+ cells was detected by flow cytometry. Results The expression of CD47 in AML patients was higher than that in the healthy control. CD47 was expressed in all FAB (French-American-British) subtypes of AML. No significant difference in CD47 expression among different FAB subtypes was found (F= 0.545, P > 0.05). Among the 37 patients with CD34+ CD38- CD47hi, 17 (46%) were FLT3-ITD negative, and 20 (54%) were FLT3-ITD positive. Among the 100 patients with CD34+ CD38- CD47hi, 63 (63%) cases were FLT3-ITD negative, 37 (37%) cases were FLT3-ITD positive. The rate of FLT3-ITD positive in patients with CD34+ CD38- CD47lo had no statistical difference compared with patients with CD34+ CD38- CD47hi (χ 2= 3.79, P > 3.79). The CD34+ CD38- CD47lo or CD34+ CD38- CD47hi which was selected by FACS, was inoculated with the methylcellulose plate containing agarose for 12 days, and CD34+ CD38- CD47lo cells could form CFU. The NSG mouse transplantation experiment showed that CD34+ CD38- CD47lo cells could be reconstructed hematopoiesis, and CD34+ CD38- CD47hi implantation failed. Conclusion CD34+ CD38- CD47hi could enrich LSC, which may be a potential marker to detect minimal residual disease. Key words: Leukemia, myelogenous, acute; Antigens, CD47; Colony-forming units assay

Motivation of Chinese patients with chronic myelogenous leukemia who have stopped the tyrosine kinase inhibitor

Objective To analyze the motivation of Chinese patients with chronic myelogenous leukemia (CML) who have stopped the tyrosine kinase inhibitor (TKI). Methods Forty-seven CML patients who have stopped TKI provided informed consent prior to their participation in the study. These patients were divided into relapse and non-relapse group at the endpoint of the observation. None of the patients received any CML-associated therapies after TKI cessation. The reasons of withdrawal were analyzed statistically. Results The reasons for cessation included patient's request due to cost (59.57%, 28/47), patient's plan to getting pregnant (8.52%, 4/47), side-effect of TKI (23.40%,11/47) and other reasons (8.52%, 4/47). At the endpoint of observation, 23 patients suffered molecular relapse. Among them, 15 cases (65.22%) were due to cost; 1 case (4.35%) was due to getting pregnant, 5 cases (21.74%) were due to side-effect and 2 cases (8.69%) were due to other reasons. There was more frequency relapse in the group of insufficient cost. Conclusion The motivation of Chinese CML patients who have stopped TKI might show impact on the outcome, and the motivation is mainly related with history of drug reduction and withdrawal. Key words: Leukemia, myelogenous, chronic; Treatment-free remission; Withdrawal

T Cells Deficient in Diacylglycerol Kinase ζ Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia.

Efforts to improve the efficacy of adoptive T-cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the antileukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ-/-) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKζ-/- T cells relied partly on induction of sustainable host T-cell immunity. Transferring DGKζ-deficient T cells increased the levels of IFNγ and other cytokines in recipient mice, especially with coadministration of anti-PD-L1. Overall, our results offered evidence that targeting DGKζ may leverage the efficacy of adoptive T-cell and immune checkpoint therapies in leukemia treatment. Furthermore, they suggest that DGKζ targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade. Cancer Res; 77(20); 5676-86. ©2017 AACR.

Frontline treatment of AML in adults.

Despite recent progress in diagnosis and leukemogenesis based on genomic landscapes in acute myelogenous leukemia (AML), advances in AML treatment lag behind. Over the past four decades, combination chemotherapy with anthracycline and cytarabine remains the standard induction therapy. Subsequent post-remission consolidation therapy stratifies patients into favorable-risk, intermediate-risk, and unfavorable-risk groups to assign post-remission therapies based on cytogenetic abnormalities and molecular mutations. Allogeneic stem-cell transplant decreases the risk of AML recurrence compared to standard chemotherapy, but it also raises the risk of serious complications. Recent large collections of matched genomic and clinical data may assist in selecting the best individualized therapy for each AML patient. Emerging evidence indicates that molecularly targeted therapies such as FLT3 and IDH inhibitors may be effective in distinct AML subtypes, providing further rationale for a personalized medicine approach. An umbrella trial, such as "BEAT AML Master Trial," designed to offer novel targeted therapy to AML patients based on their genetic characteristics, will be launching worldwide in the near future.

Polyphyllin D inhibits proliferation of K562 on human leukemia cells by inducing apoptosis and differentiation

Objective To investigate the inhibitory effect of polyphyllin D on the proliferation of human chronic myelogenous leukemia (CML) cell line K562 cells and its mechanism. Methods Methyl thiazolyl thiazolium (MTT) assay was used to evaluate the inhibition effect of polyphyllin D on the proliferation of K562 cells. Flow cytometry was used to determine the effect of polyphyllin D on the apoptosis of K562 cells. The related proteins were analyzed by Western blotting. Results The MTT assay showed that polyphyllin D obviously inhibited the growth of K562 cells. The hemi-inhibitory concentration (IC50) of 24 hours for the K562 cells was (0.8±0.1)μmol/L. Flow cytometric results demonstrated that polyphyllin D significantly induced apoptosis in a dose-dependent manner, and the apoptosis rates of 0, 0.4, 0.8, 1.2 μmol/L polyphyllin D were (1.73±0.33)%, (14.47±2.57)%, (24.10±3.52)%, (31.51±4.09)% after 24 hours, with a significant difference (F=58.231, P<0.001). Western blotting showed that polyphyllin D significantly down-regulated the expression of Bcl-2, and this was accompanied by up-regulation of Bax, decrease of the Bcl-2/Bax ratio, up-regulation of cytochrome c and activation of caspase-3. Otherwise, polyphyllin D obviously induced monocyte differentiation by increasing CD14 expression on the surface of K562 cells. Conclusion Polyphyllin D can significantly inhibit the proliferation of K562 cells, and the mechanism may be realized by inducing apoptosis and promoting monocyte differentiation. Key words: Leukemia; Apoptosis; Cell differentiation; Polyphyllin D