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BAG3 gene silencing sensitizes leukemic cells to Bortezomib-induced apoptosis.

Proteasome inhibition has emerged as a powerful option for the treatment of a number of malignancies including leukemias. However, Bortezomib showed limited single‐agent activity for patients with leukemia. Here, we report for the first time that Bortezomib up‐regulated a novel antiapoptotic protein, BAG3, in human leukemic cells. BAG3 gene knockdown with shRNA greatly potentiated the generation of apoptosis by Bortezomib in leukemia cells. Furthermore, BAG3 silencing enhanced the antitumor activity of Bortezomib dramatically in a nude mouse model. Our results indicate that knocking down BAG3 gene is a promising new approach to enhance the therapeutic potency of Bortezomib in leukemia.

LY294002 inhibits leukemia cell invasion and migration through early growth response gene 1 induction independent of phosphatidylinositol 3-kinase-Akt pathway

LY294002 (LY29) is a commonly used pharmacologic inhibitor of the phosphatidylinositol 3-kinase (PI3K) and has shown antitumorigenic effect both in vivo and in vitro. Both LY29 and its inactive analogue, LY303511 (LY30), significantly up-regulated early growth response gene 1 (Egr-1) expression in HL-60 leukemic cells. However, wortmannin, another commonly used PI3K inhibitor, was not able to induce Egr-1 at the dose that completely blocked Akt phosphorylation. LY29 markedly decreased the invasive cells number through Matrigel and human umbilical vein endothelial cells (HUVECs) compared with the controls. Moreover, the inhibitory effects could be significantly abolished by Egr-1 gene silencing with siRNA technology. Our results indicated for the first time that LY29 could suppress leukemia cell invasion and migration at least in part through up-regulation of Egr-1, independent of its PI3K-Akt inhibitory activity. These data provide a novel explanation for the anticancer properties of LY29 in leukemias.

Elevated plasma levels of vascular endothelial growth factor is associated with marked splenomegaly in chronic myeloid leukemia.

Recent investigations support the idea that angiogenesis is involved in the pathophysiology of hematologic malignancies, including chronic myeloid leukemia (CML). The aim of the present study was to evaluate plasma levels of VEGF and bFGF in a cohort of 51 chronic-phase CML patients at the time of diagnosis, as well as to investigate the effect of imatinib therapy on VEGF amounts in CML patients. Plasma VEGF levels were significantly higher in patients studied as compared with the 20 healthy subjects (p<0.001), the median plasma VEGF level detected in patients analysed and healthy controls was 433.4 pg mL−1 (range 65.2–2452.7 pg mL−1) and 81.6 pg mL−1 (range 44.2–338.7 pg mL−1), respectively. On the other hand, no difference in bFGF plasma levels could be found between chronic-phase CML patients and the control group. There were significant associations between plasma VEGF levels and some characteristics of patients evaluated, with trends for higher VEGF values in patients with enlarged spleens (p = 0.02) and those with higher platelet count (p<0.001). Of the patients, 11 received imatinib treatment. The initial VEGF levels markedly decreased after 6 months of imatinib therapy in each patient (p<0.001). These data support the important pathophysiological role of VEGF in CML. Further studies aiming to explore the detailed angiogenic profile of CML may help in developing new therapeutic strategies for this myeloproliferative disorder.

Heterogeneous leukemic clones identified by NPM1 mutation analysis in patient with acute monocytic leukemia

Abstract NPM1 mutation is the most common molecular abnormality in patients with acute myeloid leukemia (AML), especially normal karyotype AML (NK-AML), and is associated with a favorable prognosis in the absence of concomitant FLT3-ITD. Like other molecular abnormalities such as FLT3-ITD, C/EBPα and c-Kit mutation, NPM1 mutation normally presents as a recurrent molecular abnormality. The NPM1 mutation is generally used as a molecular marker in the prognosis evaluation of a patient with AML. Here, we report a different case. He was first diagnosed with NPM1 mutation-positive acute monocytic leukemia. However, he achieved no remission, but the NPM1 mutation dramatically became negative after induction chemotherapy. Finally, he achieved complete remission after salvage chemotherapy and the NPM1 mutation was still negative. To our knowledge, this is a rare case according to the worldwide published literature.

Thalidomide inhibits leukemia cell invasion and migration by upregulation of early growth response gene 1.

Thalidomide has been shown to exert its antitumor activity through the significant effects on microenvironment and immunomodulatory properties. In this study, 10 μM thalidomide treatment markedly increased the expression of the early growth response gene 1 (Egr-1) at both mRNA and protein levels in HL-60 leukemic cells. Thalidomide treatment significantly decreased the invasive cells number through Matrigel and human umbilical vein endothelial cells when compared with the controls. Moreover, the inhibitory effects could be markedly abolished by Egr-1 gene silencing with siRNA technology. Our data indicated thalidomide could suppress leukemia cell invasion and migration by upregulation of Egr-1, suggesting a novel mechanism of thalidomide in the treatment of leukemia. Further investigations are needed to explore the detailed mechanism of Egr-1 induction by thalidomide and the downstream pathways involved in the regulation of leukemia cell invasion.

Bortezomib in combination with dexamethasone for a young multiple myeloma with t(8; 14)

Multiple myeloma (MM) is a malignant plasma cell disrder which generally occurs in older adults with a peak f age between 60 and 70 [1]. Approximately, only 2% of atients with multiple myeloma are younger than the age of 0 [2]. It is extremely rarely seen in patients younger than the ge of 30. In recent years, proteasome inhibitor bortezomib as shown an encouraging effect in the treatment of multiple yeloma. Recently, a 23-year-old male of multiple myeloma ith chromosomal translocation t(8; 14) is noted. He was reated with bortezomib in combination with dexamethasone ollowed by autologous peripheral hematopoietic stem cell ransplantation and exhibited a significant improvement.

Chronic myelomonocytic leukaemia associated with acquired haemophilia A: case report and literature review.

Chronic myelomonocytic leukaemia (CMML) and acquired haemophilia A (AHA) are rare blood disorders. CMML is a clonal haematopoietic stem cell disorder, characterized by absolute monocytosis in the peripheral blood that persists for at least 3 months. According to the World Health Organization (WHO) classification, CMML is classified as a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN). The incidence of CMML is lower than 10 cases per million people per year [1]. AHA is a bleeding disorder caused by autoantibodies against factor VIII (FVIII) with an estimated incidence of 1.48 cases per million people per year [2]. Although the underlying disorder cannot be identified in 50% of the patients [3], it is believed that AHA is associated with autoimmune disorders, malignancies, pregnancy, dermatological disorders and drug reactions. In this article, we describe a case of AHA in an old man with CMML; it is the fourth case of CMML associated with AHA to be reported in the literature, which makes the findings rare and valuable.

Plasma cell labeling index correlates with deletion of 13q14 in multiple myeloma.

Multiple myeloma (MM) is characterized by complex genetic and chromosomal abnormalities involving both numerical and structural aberrations, which have clinical prognostic value. The plasma cell labeling index (PCLI) is one of the most important prognostic factors in newly diagnosed MM, and indicates plasma cell proliferative capacity. In this study, we determined the PCLI and the deletion of 13q14, retinoblastoma-1 gene (RB-1), 1p13, and 17p13, 1q21 amplification, and IgH rearrangements in 42 newly diagnosed patients with MM. A high PCLI was observed in 18 patients (42.9%), and the del(13q14) was present in 25 patients (59.5%), del(RB-1) in 23 patients (54.8%), del(17p13) in eight patients (19.1%), amp(1q21) in 23 patients (54.7%), del(1p13) in 17 patients (40.5%), and IgH rearrangements in 28 patients (66.7%). We further detected the IgH translocation partners: t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23) in 19, 15, and five patients, respectively. The PCLI had a significant correlation with del(13q14) (p = 0.006), but no correlation with other chromosome abnormalities or clinical and laboratory features (p > 0.05). The PCLI was higher among patients with del(13q14), and patients with a high PCLI had a short time to disease progression. In conclusion, PCLI is a powerful and independent prognostic parameter in newly diagnosed MM, and correlates with del(13q14).

c-MYC depletion potentiates cisplatin-induced apoptosis in head and neck squamous cell carcinoma: involvement of TSP-1 up-regulation

c-MYC, the human homolog of a retroviral oncogene, was identified 25 years ago. Given the crucial role of c-MYC in cell proliferation and death and, moreover, in the development and maintenance of many cancers, the potential therapeutic benefits of c-MYC inhibition in human malignancies are self-evident. However, since c-MYC is deregulated and overexpressed in such a broad range of human cancers and it regulates approximately 10%–15% of all cellular genes, it is difficult to determine what kinds of tumor are the appropriate candidates for this anticancer strategy [1, 2]. Recent investigations highlight the tumorigenic role of c-MYC in head and neck squamous cell carcinoma (HNSCC). Koehn et al. applied proteomic technologies to analyze the proteome of 10 patients with human oral squamous cell carcinoma and reported that, among 350 different gene products identified, 20 proteins showed deranged levels in this disease and are potentially involved in tumor growth and metastasis. By pathway analysis, the authors found 8 of the 16 up-regulated gene products to be linked to three main locus genes, one of which is c-MYC [3]. Moreover, cancerous inhibitor of protein phosphatase 2A (CIP2A) a novel oncoprotein, was first identified to be required for the development of human malignancies in HNSCC model. Importantly, CIP2A plays its oncogenic role mainly through stabilizing c-MYC protein [4]. All these information provide the rationale to evaluate the therapeutic potential of targeting aspects of c-MYC activity in HNSCC. Thrombospondin-1 (TSP-1) was recently identified as a target gene of c-MYC [5]. It is a multimodular, 420-kDa, letters to the editor Annals of Oncology

All-trans retinoic acid induces Thrombospondin-1 expression in acute promyelocytic leukemia cells though down-regulation of its transcription repressor, c-MYC oncoprotein

Thrombospondin-1 (TSP-1) was found to mediate the therapeutic effects of all-trans retinoic acid (ATRA) for leukemia. The aim of the present study was to evaluate the role of c-MYC, a key transcription factor that contributes to the genesis of many human tumors, in TSP-1 induction by ATRA in acute promyelocytic leukemia (APL). ATRA treatment markedly increased TSP-1 level and inhibited c-MYC expression in NB4 APL leukemic cells compared with controls. Promoter assays indicated that c-MYC responsive element is functional relevant to the induction of TSP-1 promoter activity by ATRA. c-MYC recruitment to TSP-1 promoter was dramatically decreased in NB4 cells following ATRA treatment. shRNA-mediated inhibition of c-MYC resulted in a marked up-regulation of endogenous TSP-1 expression. Moreover, transient over-expression of c-MYC totally abolished TSP-1 induction by ATRA in NB4 cells. Collectively, our results indicate that ATRA induces TSP-1 expression in APL cells though down-regulation of its transcription repressor, c-MYC oncoprotein.