Hes1 Controls Proliferation and Apoptosis in Chronic Lymphoblastic Leukemia Cells by Modulating PTEN Expression.

Hairy and enhancer of split homolog-1 (HES1), regulated by the Notch, has been reported to play important roles in the immune response and cancers, such as leukemia. In this study, we aim to explore the effect of HES1-mediated Notch1 signaling pathway in chronic lymphocytic leukemia (CLL). Reverse transcription quantitative polymerase chain reaction and Western blot assay were conducted to determine the expression of HES1, Notch1, and PTEN in B lymphocytes of peripheral blood samples of 60 CLL patients. We used lentivirus-mediated overexpression or silencing of HES1 and the Notch1 signaling pathway inhibitor, MW167, to detect the interaction among HES1, Notch1, and PTEN in CLL MEC1 and HG3 cells. MTT assay and flow cytometry were employed for detection of biological behaviors of CLL cells. HES1 and Notch1 showed high expression, but PTEN displayed low expression in B lymphocytes of peripheral blood samples of patients with CLL in association with poor prognosis. HES1 bound to the promoter region of PTEN and reduced PTEN expression. Overexpression of HES1 activated the Notch1 signaling pathway, thus promoting the proliferation of CLL cells, increasing the proportion of cells arrested at the S phase and limiting the apoptosis of CLL cells. Collectively, HES1 can promote activation of the Notch1 signaling pathway to cause PTEN transcription inhibition and the subsequent expression reduction, thereby promoting the proliferation and inhibiting the apoptosis of CLL cells.

Overexpression of long non-coding RNA HOTAIR predicts a poor prognosis in patients with acute myeloid leukemia.

The long non-coding RNA, HOX transcript antisense intergenic RNA (HOTAIR), has been indicated to have involvement in a number of cancers, however, its role in acute myeloid leukemia (AML) is unknown. The present study aimed to investigate the pattern of HOTAIR expression in AML and to evaluate its clinical significance in tumor progression. Quantitative polymerase chain reaction was performed to examine the HOTAIR expression in mononuclear cells from the bone marrow (BM) or peripheral blood specimens of 85 patients with newly diagnosed AML. The association of HOTAIR expression with the clinicopathological factors and prognosis of AML patients was statistically analyzed. The expression of HOTAIR was significantly upregulated in the AML patients compared with the healthy controls (mean expression value, 3.87±0.29 vs. 1.28±0.09; P<0.001), and markedly decreased in the patients post-treatment compared with pre-treatment (4.76±0.47 vs. 2.81±0.27; P<0.001). Moreover, high levels of HOTAIR were associated with higher white blood cell and BM blast counts (P<0.001 and P=0.001, respectively), and lower hemoglobin and platelet counts (P=0.007 and 0.001, respectively). Patients with a high level of HOTAIR expression had relatively poor overall survival (OS; 20.5 vs. 32.1 months, P=0.001) and relapse-free survival (21.5 vs. 33.6 months, P=0.001) times compared with those with a low level of HOTAIR expression. These data demonstrated that HOTAIR expression was upregulated in newly diagnosed AML patients and was associated with leukemic burden, and DFS and OS times. HOTAIR may represent a biomarker of a poor prognosis and is a potential therapeutic target for AML treatment.

Subcutaneous Administration of Bortezomib in Combination with Thalidomide and Dexamethasone for Treatment of Newly Diagnosed Multiple Myeloma Patients.

OBJECTIVE: To investigate the efficacy and safety of the treatment of the newly diagnosed multiple myeloma (MM) patients with the therapy of subcutaneous (subQ) administration of bortezomib and dexamethasone plus thalidomide (VTD) regimen. METHODS: A total of 60 newly diagnosed MM patients were analyzed. 30 patients received improved VTD regimen (improved VTD group) with the subQ injection of bortezomib and the other 30 patients received conventional VTD regimen (VTD group).The efficacy and safety of two groups were analyzed retrospectively. RESULTS: The overall remission (OR) after eight cycles of treatment was 73.3% in the VTD group and 76.7% in the improved VTD group (P > 0.05). No significant differences in time to 1-year estimate of overall survival (72% versus 75%, P = 0.848) and progression-free survival (median 22 months versus 25 months; P = 0.725) between two groups. The main toxicities related to therapy were leukopenia, neutropenia, thrombocytopenia, asthenia, fatigue, and renal and urinary disorders. Grade 3 and higher adverse events were significantly less common in the improved VTD group (50%) than VTD group (80%, P = 0.015). CONCLUSIONS: The improved VTD regimen by changing bortezomib from intravenous administration to subcutaneous injection has noninferior efficacy to standard VTD regimen, with an improved safety profile and reduced adverse events.

Adiponectin signals through Adiponectin Receptor 1 to reverse imatinib resistance in K562 human chronic myeloid leukemia cells.

Adiponectin, a member of adipokines, is a functional ligand for Adiponectin Receptor-1 (AdipoR1) and Adiponectin Receptor-2 (AdipoR2), and has been found to be linked to the risk of CML. Imatinib has undoubtedly revolutionised the management and outcome of chronic myeloid leukemia (CML), however imatinib resistance has been recognized as a major problem in CML therapy. In this study, we first established imatinib-resistant K562 CML cells, and then evaluated the effect of Adiponectin in reversing imatinib resistance. The data presented here demonstrated that Adiponectin was able to reverse K562 resistance to imatinib in vitro and in vivo. Additional data with molecular approaches suggested that the reversion of Adiponectin in imatinib resistance signals through AdipoR1 but not AdipoR2 to downregulate Bcr-Abl expression and effect in imatinib-resistant K562 CML cells. Taken together, our data showed that Adiponectin can reverse imatinib resistance in CML, and to a certain extent elucidate the mechanism of Adiponectin reversing imatinib resistance that may provide a new and promising approach in imatinib resistance management in CML therapy.