The role of the genetic abnormalities, epigenetic and microRNA in the prognosis of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is increased proliferation of B-cells with peripheral blood and bone marrow involvement, which is usually observed in older people. Genetic mutations, epigenetic changes and miRs play a role in CLL pathogenesis. Del 11q, del l17q, del 6q, trisomy 12, p53 and IgVH mutations are the most important genetic changes in CLL. Deletion of miR-15a and miR-16a can increase bcl2 gene expression, miR-29 and miR-181 deletions decrease the expression of TCL1, and miR-146a deletion prevents tumor metastasis. Epigenetic changes such as hypo- and hypermethylation, ubiquitination, hypo- and hyperacetylation of gene promoters involved in CLL pathogenesis can also play a role in CLL. Expression of CD38 and ZAP70, presence or absence of mutation in IgVH and P53 mutation are among the factors involved in CLL prognosis. Use of monoclonal antibodies against surface markers of B-cells like anti-CD20 as well as tyrosine kinase inhibitors are the most important therapeutic approaches for CLL.

MicroRNAs as prognostic biomarker and relapse indicator in leukemia

Despite significant progress in the treatment of different types of leukemia, relapse remains a challenging clinical problem that is observed in a number of patients who are often resistant to chemotherapy and exhibit multi-drug resistance. Identification of new functional biomarkers, including microRNAs, is essential to determine prognosis and relapse at the time of diagnosis. The aim of this study was to detect the specific microRNAs involved in predicting relapse or progression in acute and chronic leukemias, as well as their relationship with overall survival (OS) and relapse-free survival (RFS). The relevant literature was identified through a PubMed and Scholar search (2008-2016) of English-language papers using the terms Leukemia, microRNAs, survival and relapse. Different leukemia types and subtypes show specific microRNA expression profile and different changes, which can be useful in the differentiation between leukemias and evaluation of relapse at the time of diagnosis. Altered microRNA expression profiles can turn these molecules into oncogenes or tumor suppressors, which affect the expression of relapse-related genes. Therefore, monitoring of specific microRNA expression profiles from diagnosis and during follow-up of patients can contribute to the assessment of outcome and determination of relapse and prognosis of leukemic patients (AU)

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MicroRNAs as prognostic biomarker and relapse indicator in leukemia.

Despite significant progress in the treatment of different types of leukemia, relapse remains a challenging clinical problem that is observed in a number of patients who are often resistant to chemotherapy and exhibit multi-drug resistance. Identification of new functional biomarkers, including microRNAs, is essential to determine prognosis and relapse at the time of diagnosis. The aim of this study was to detect the specific microRNAs involved in predicting relapse or progression in acute and chronic leukemias, as well as their relationship with overall survival (OS) and relapse-free survival (RFS). The relevant literature was identified through a PubMed and Scholar search (2008-2016) of English-language papers using the terms Leukemia, microRNAs, survival and relapse. Different leukemia types and subtypes show specific microRNA expression profile and different changes, which can be useful in the differentiation between leukemias and evaluation of relapse at the time of diagnosis. Altered microRNA expression profiles can turn these molecules into oncogenes or tumor suppressors, which affect the expression of relapse-related genes. Therefore, monitoring of specific microRNA expression profiles from diagnosis and during follow-up of patients can contribute to the assessment of outcome and determination of relapse and prognosis of leukemic patients.

Signaling and molecular basis of bone marrow niche angiogenesis in leukemia

Angiogenesis, the process of blood vessel formation, is necessary for tissue survival in normal and pathologic conditions. Increased angiogenesis in BM niche is correlated with leukemia progression and resistance to treatment. Angiogenesis can interfere with disease progression and several angiogenic (such as vascular growth factors) as well as anti-angiogenic factors (i.e. angiostatin) can affect angiogenesis. Furthermore, miRs can affect the angiogenic process by inhibiting angiogenesis or increasing the expression of growth factors. Given the importance of angiogenesis in BM for maintenance of leukemic clones, recognition of angiogenic and anti-angiogenic factors and miRs as well as drug resistance mechanisms of leukemic blasts can improve the therapeutic strategies. We highlight the changes in angiogenic balance within the BM niche in different leukemia types. Moreover, we explored the pathways leading to drug resistance in relation to angiogenesis and attempted to assign interesting candidates for future research (AU)

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Central nervous system niche involvement in the leukemia

Central nervous system (CNS) impairment is commonly involved in leukemia, as it can be observed upon onset or relapse of the disease. It is associated with poor prognosis and is a challenging clinical problem. The objective of this paper was to provide a characterization of the CNS niche in leukemia, to elucidate the culprits of CNS involvement, including diagnostic micro RNAs (miRs) and early leukemia prognosis. CNS niche is a proper location for homing of leukemic stem cells, thus representing a candidate target in the treatment of leukemia. Recent advances in the study of leukemia hallmarks have enlightened miRs as novel biomarkers for diagnosis and detection of CNS involvement in leukemia, thus providing the opportunity to develop novel therapeutic approaches. Given the importance of prognosis and early diagnosis of CNS involvement in leukemias as well as the severe side effects of current treatments, diagnostic and therapeutic approaches should focus on identification and inhibition of the factors contributing to CNS involvement, including CXCR3, P-selectin glycoprotein ligand-1 and MCP1. MiRs such as miR-221 and miR-222 are emerging as potential tools for an innovative non-invasive therapy of CNS in leukemia affected patients (AU)

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Twist as a new prognostic marker in hematological malignancies

Twist proteins are members of basic helix-loop-helix family and are major regulators of embryogenesis. In adult humans, Twist proteins are mainly expressed in precursor cells, including myogenic, osteoblastic, chondroblastic and myelomonocytic lineages, maintaining their undifferentiated state. In addition, they play important roles in lymphocyte function and maturation. Recently, several studies have reported regulatory roles for Twist in the function and development of hematopoietic cells as well as in survival and development of numerous hematological malignancies. It is activated by numerous signal transduction pathways, including Akt, nuclear factor κB, Wnt, signal transducer and activator of transcription 3, mitogen-activated protein kinase and Ras signaling. Activated Twist has an anti-apoptotic role and protects cancer cells from apoptotic cell death. In addition, overexpression of Twist promotes the process of epithelial-mesenchymal transition, which has an essential role in cancer metastasis. Hereby, we review the aberrant expression of Twist in hematopoietic malignancies such as leukemias, lymphomas and myelodysplastic syndrome, which is related with poor prognosis and drug resistance in these disorders. Inactivation of Twist by small RNAs technology or chemotherapeutic inhibitors targeting Twist and upstream or downstream molecules of Twist signaling pathways may be helpful in management of disease to improve treatment strategies in malignancies (AU)

No disponible

Signaling and molecular basis of bone marrow niche angiogenesis in leukemia.

Angiogenesis, the process of blood vessel formation, is necessary for tissue survival in normal and pathologic conditions. Increased angiogenesis in BM niche is correlated with leukemia progression and resistance to treatment. Angiogenesis can interfere with disease progression and several angiogenic (such as vascular growth factors) as well as anti-angiogenic factors (i.e. angiostatin) can affect angiogenesis. Furthermore, miRs can affect the angiogenic process by inhibiting angiogenesis or increasing the expression of growth factors. Given the importance of angiogenesis in BM for maintenance of leukemic clones, recognition of angiogenic and anti-angiogenic factors and miRs as well as drug resistance mechanisms of leukemic blasts can improve the therapeutic strategies. We highlight the changes in angiogenic balance within the BM niche in different leukemia types. Moreover, we explored the pathways leading to drug resistance in relation to angiogenesis and attempted to assign interesting candidates for future research.

Central nervous system niche involvement in the leukemia.

Central nervous system (CNS) impairment is commonly involved in leukemia, as it can be observed upon onset or relapse of the disease. It is associated with poor prognosis and is a challenging clinical problem. The objective of this paper was to provide a characterization of the CNS niche in leukemia, to elucidate the culprits of CNS involvement, including diagnostic micro RNAs (miRs) and early leukemia prognosis. CNS niche is a proper location for homing of leukemic stem cells, thus representing a candidate target in the treatment of leukemia. Recent advances in the study of leukemia hallmarks have enlightened miRs as novel biomarkers for diagnosis and detection of CNS involvement in leukemia, thus providing the opportunity to develop novel therapeutic approaches. Given the importance of prognosis and early diagnosis of CNS involvement in leukemias as well as the severe side effects of current treatments, diagnostic and therapeutic approaches should focus on identification and inhibition of the factors contributing to CNS involvement, including CXCR3, P-selectin glycoprotein ligand-1 and MCP1. MiRs such as miR-221 and miR-222 are emerging as potential tools for an innovative non-invasive therapy of CNS in leukemia affected patients.

Twist as a new prognostic marker in hematological malignancies.

Twist proteins are members of basic helix-loop-helix family and are major regulators of embryogenesis. In adult humans, Twist proteins are mainly expressed in precursor cells, including myogenic, osteoblastic, chondroblastic and myelomonocytic lineages, maintaining their undifferentiated state. In addition, they play important roles in lymphocyte function and maturation. Recently, several studies have reported regulatory roles for Twist in the function and development of hematopoietic cells as well as in survival and development of numerous hematological malignancies. It is activated by numerous signal transduction pathways, including Akt, nuclear factor κB, Wnt, signal transducer and activator of transcription 3, mitogen-activated protein kinase and Ras signaling. Activated Twist has an anti-apoptotic role and protects cancer cells from apoptotic cell death. In addition, overexpression of Twist promotes the process of epithelial-mesenchymal transition, which has an essential role in cancer metastasis. Hereby, we review the aberrant expression of Twist in hematopoietic malignancies such as leukemias, lymphomas and myelodysplastic syndrome, which is related with poor prognosis and drug resistance in these disorders. Inactivation of Twist by small RNAs technology or chemotherapeutic inhibitors targeting Twist and upstream or downstream molecules of Twist signaling pathways may be helpful in management of disease to improve treatment strategies in malignancies.