h4>Background: /h4> The interaction of integrins and growth factor receptors in cells is tightly regulated, ensuring cell survival, proliferation, differentiation, adhesion, and migration. The IR generates reactive oxygen species, which leads to ECM remodeling and cell adhesion through the activation of proteases, soluble cytokines and growth factors. Integrins and adhesion of cells to ECM confer higher resistance to ionizing radiation and cytotoxic drug, a phenomenon known as cell adhesion mediated radiation resistance (CAM-RR) and cell adhesion mediated drug resistance (CAM-DR) . Integrins’ involvement in CML progression is well appreciated through its survival, adhesion and migration signaling. The evaluation of global genetic response (in microarray) of ionizing radiation (IR) on integrins expression has not been attempted to specify theirrole and other cell adhesion molecules (CAMs) in CML. In this study, we have compared the microarray based CAMs response in myelogenous leukemia cells onIR exposure. h4>Results: /h4>: Results revealed differential regulation of many CAMs, with strongest expression of integrin β2 (CD18), whose role has not been fully appreciated in CML due to low level of expression. However, the synergistic LiCl(GSK3β inhibitor) and IR treatment significantly upregulates CD18 expression leading to enhanced survival, cell adhesion mediated drug/radiation resistance (CAM-DR/RR) and transcription of migration related genes. These effects could be undermined in the presence of CD18 antibody. This may be one of the reasons for CML resistance to radiation therapy and its relapse upon stem cell transplantation. h4>Conclusion: /h4> This study proposes CD18 antagonist administration as an adjuvant in anti-CML therapy and other cancers in which it displays aberrant expression subsuming the contraindication of GSK3β inhibitor. Nevertheless, the CD18 mediated cell adhesion in tumor progression beckons development of improved drug regimensandidentification of diagnostic and prognostic signature for CML.

Differentiation therapy has been successfully applied clinically in cases of acute promyelocytic leukemia (APL), but few differentiation-induction agents other than all-trans retinoic acid (ATRA) have been discovered clinically. Based on our previously reported neuritogenic differentiation activity of synthetic dimeric derivatives of securinine, we explored the leukemia differentiation-induction activity of such as compound, SN3-L6. It was found that SN3-L6 induces transdifferentiation of both acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML) cells but unexpectedly, a new transdifferentiation pathway from APL cells to morphologically and immunologically normal megakaryocytes and platelets were discovered. SN3-L6 fails to induce transdifferentiation of ATRA-produced mature granulocytes into megakaryocytes, indicating its selectivity between mature and immature cells. SN3-L6 induces CML K562 cells to transdifferentiate into apoptotic megakaryocytes but without platelet formation, indicating a desirable selectivity between different leukemia cells. Our data illuminate a differentiation gap between AML cells and platelets, and promises applications in leukemia differentiation therapy strategy.

Acute megakaryocytic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML), which is challenging to diagnose due to frequent myelofibrosis (MF) and a low percentage of blast cells. In the present study, clinical characteristics and experimental observations in 9 adult patients diagnosed with AMKL, who were recruited by the Sino-U.S. Shanghai Leukemia Co-operative Group, were analyzed in order to summarize the diagnostic experience and provide recommendations on diagnosing AMKL. All the patients were diagnosed according to the 2008 World Health Organization diagnostic criteria. The mean age of the patients with AMKL was 59 years (range, 53-68 years). A total of 8 patients had different degrees of anemia, and 2 patients had <5% marrow blasts present in the bone marrow; however, the percentage of positive cells with cluster of differentiation (CD)41 and CD61 expression was >20%, as demonstrated by flow cytometry. A total of 6 patients were positive for platelet-specific antigens, as indicated by immunocytochemistry. Furthermore, 7 patients presented with moderate or marked MF, as demonstrated by a bone marrow biopsy. Karyotypic analysis indicated that 6 patients had abnormal karyotypes. Only 1 patient exhibited the Janus kinase 2V617F mutation. Treatment efficiency was notably poor, with a median survival time of 6.0 months (range, 1.1-24.0 months). In conclusion, the diagnosis of AMKL requires a combination of the results of bone marrow smears and bone marrow biopsy, immunophenotype or immunohistochemistry. We recommend that routine immunophenotypic analysis should include the CD41 and CD61 markers for diagnosing acute leukemia when bone marrow morphology does not indicate the diagnosis.

Cell-derived microparticles (MPs) have been described as vital contributors to the inflammatory process. However, its role in the periodontal disease pathogenesis remains unclear. Therefore, we aimed to detect the presence neutrophil (CD66b+) and platelet (CD41b+) derived microparticles in gingival crevicular fluid from individuals having periodontitis aggravated by type 2 diabetes. Twelve patients (56.2 ±7.2 yrs) with severe form of chronic periodontitis aggravated by type 2 diabetes were included. Clinical and metabolic data were gathered. Gingival crevicular fluid was collected using filter strips from deep and shallow sites. MPs were detected by flow cytometry according to their size (< 1 µm) and the expression of surface markers (CD66b for neutrophil-derived MPs and CD41b for platelet-derived MPs). All samples were positive for the antibodies. Median levels of CD66b+ MPs and CD41b+ MPs were, respectively, 3,677.0 (2,553.2 - 9,059.8) MP/µL and 520.7 (432.9 - 766.1) MP/µL in deep sites. In shallow sites, the corresponding values were 2,644.9 (1,451.5 - 3,858.9) MP/µL and 371.2 (287.2 - 692.7) MP/µL. There was no significant difference between deep and shallow sites (p>0.05). In conclusion, this study reported the presence of neutrophil and platelet derived microparticles in gingival crevicular fluid from individuals having severe periodontitis and type 2 diabetes.

Primary myelofibrosis (PMF) is characterized by bone marrow fibrosis, myeloproliferation, extramedullary hematopoiesis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleens of individuals with PMF contain large numbers of atypical megakaryocytes that are postulated to contribute to fibrosis through the release of cytokines, including transforming growth factor (TGF)-β. Although the Janus kinase inhibitor ruxolitinib provides symptomatic relief, it does not reduce the mutant allele burden or substantially reverse fibrosis. Here we show through pharmacologic and genetic studies that aurora kinase A (AURKA) represents a new therapeutic target in PMF. Treatment with MLN8237, a selective AURKA inhibitor, promoted polyploidization and differentiation of megakaryocytes with PMF-associated mutations and had potent antifibrotic and antitumor activity in vivo in mouse models of PMF. Moreover, heterozygous deletion of Aurka was sufficient to ameliorate fibrosis and other PMF features in vivo. Our data suggest that megakaryocytes drive fibrosis in PMF and that targeting them with AURKA inhibitors has the potential to provide therapeutic benefit.