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CHARACTERIZATION OF THE UNFOLDED PROTEIN RESPONSE ROLE IN DIFFERENTIATION THERAPY OF ACUTE MYELOID LEUKEMIAS
No full textIntroduction. Acute myeloid leukemia (AML) is caused by the clonal
expansion of hematopoietic myeloid precursors blocked at different
stages of differentiation. A subtype of AML, acute promyelocytic
leukemia (APL), is a paradigm of differentiation therapy since all-transretinoic
acid (ATRA)-based treatments are able to induce leukemic blast
terminal differentiation, leading to clinical remission in the majority of
APL patients. However, ATRA can lead to systemic toxicity and relapses
after initial remission followed by resistance. Furthermore APL
accounts for about 10-15% of AML cases and non-APL AML respond
only very slightly to ATRA. Thus the search for a strategy to further sensitize
AML cells to ATRA is highly needed. ATRA induces differentiation
of APL blasts to granulocytes that are secretory cells since they are
characterized by the presence of secretory granules containing peptides
indispensable for their role in the immune response. The majority of
proteins secreted or reside
microRNA biogenesis pathway as therapeutic target for human disease and cancer
No full textThe deregulation of miRNAs expression and activity is frequently observed in a wide variety of human pathologies including cancer. Accordingly, growing evidence indicates that the targeting of microRNAs biogenesis and pathways is emerging as a central tool for the development of novel RNA-based drugs and therapies to defeat diseases in humans. In this review we describe the various strategies that can be used to target the microRNAs and specific RNA-binding proteins, involved in the regulation of their production, localization, stability and activity, in human cancer and cardiovascular diseases. We also focus on the efforts that are currently made to enhance the potency and stability of these therapeutic agents and their delivery to modulate in vivo microRNAs pathways. Finally, we present structural data on proteins that belong to the microRNA pathway for small molecules-based target therapy design
The methylated DNA immunoprecipitation [MeDIP] to investigate the epigenetic remodeling in cell fate determination and cancer development
No full textEpigenetic mechanisms such as DNA methylation, posttranslational modifications of histone proteins, remodeling of nucleosomes, and the expression of noncoding RNAs contribute to the regulation of gene expression for the cell fate determination and tissue development. The disruption of these epigenetic mechanisms, in conjunction with genetic alterations, is a decisive element for cancer development and progression. The cancer phenotype is characterized by global DNA hypomethylation and gene-specific hypermethylation. The methylated DNA immunoprecipitation [MeDIP] is a useful approach currently used to clarify the functional consequences of DNA methylation on cell fate determination and cancer development
Lymphoid EVA1 expression is required for DN1-DN3 thymocytes transition.
No full textBACKGROUND:Thymus organogenesis and T lymphocyte development are accomplished together during fetal life. Proper development and maintenance of thymus architecture depend on signals generated by a sustained crosstalk between developing thymocytes and stromal elements. Any maturation impairment occurring in either cellular component leads to an aberrant thymic development. Gene expression occurring during T lymphocyte differentiation must be coordinated in a spatio-temporal fashion; one way in which this is achieved is through the regulation by cell-cell adhesion and interactions. PRINCIPAL FINDINGS:We examined the role played by Epithelial V-like Antigen 1 (EVA1), an Ig adhesion molecule expressed on thymus epithelial cells (TEC) and immature thymocytes, in T cell development by employing RNA interference in vitro and in vivo models. Fetal liver derived haematopoietic progenitors depleted of Eva1, displayed a delayed DN1-DN3 transition and failed to generate CD4CD8 double positive T cells in OP9-DL1 coculture system. In addition, we could observe a coordinated Eva1 up-regulation in stromal and haematopoietic cells in coculture control experiments, suggesting a possible EVA1 involvement in TEC-haematopoietic cells crosstalk mechanisms. Similarly, Rag2-gamma c double knock out mice, transplanted with Eva1 depleted haematopoietic progenitors displayed a 10-fold reduction in thymus reconstitution and a time delayed thymocytes maturation compared to controls. CONCLUSIONS:Our findings show that modulation of Eva1 expression in thymocytes is crucial for lymphocyte physiological developmental progression and stromal differentiation
Identification of post-transcriptional regulatory networks during myeloblast-to-monocyte differentiation transition
Get PDFTreatment of leukemia cells with 1, 25-dihydroxyvitamin D3 may overcome their differentiation block and lead to the transition from myeloblasts to monocytes. To identify microRNA-mRNA networks relevant for myeloid differentiation, we profiled the expression of mRNAs and microRNAs associated to the low- and high-density ribosomal fractions in leukemic cells and in their differentiated monocytic counterpart. Intersection between mRNAs shifted across the fractions after treatment with putative target genes of modulated microRNAs showed a series of molecular networks relevant for the monocyte cell fate determination, as for example the post-transcriptional regulation of the Polo-like kinase 1 (PLK1) by miR-22–3p and let-7e-5p
Argonaute 2 as novel molecular determinant for myeloid differentiation.
Get PDFmicroRNAs (miRNAs) are emerging as crucial factors for the establishment of complex regulatory circuitries involved in the regulation of hematopoietic cell fate determination. These small non-coding RNAs to exert their functional activity are assembled in RNA-induced silencing complexes (RISCs), where a member of Argonaute (Ago) family of proteins plays a central role in miRNA-mRNA target interaction and gene silencing. In human cells the miRNAs-Ago complex can also localize in the nucleus where Ago proteins can associate with promoter gene sequences to impact heterochromatin genomic structure and transcriptional silencing (Janowski BA et al., 2006; Meister G., 2013).
By using human myeloid cell lines and acute myeloid leukemia (AML) primary blasts we highlight Ago2 as a new player in myeloid cell fate determination. We observed that: i) Ago2 protein levels are strongly increased during 1,25-dihydroxyvitamin D3 (D3)-induced monocyte differentiation, whereas are down-regulated during R
ARGONAUTE-2 AS NOVEL MOLECULAR TARGET FOR THE DIFFERENTIATION THERAPY OF ACUTE MYELOID LEUKEMIA CELLS
No full textIntroduction. In hematopoietic stem cells, growth and maturation of erythroid,
granulocytic, monocytic and megakaryocytic lineages are largely
controlled by unique combinations of transcription factors that cooperatively
regulate promoters and enhancers present on specific target genes.
miRNAs provide an additional level of control beyond the transcription
factors and play a central role in hematopoietic differentiation through the
establishment of complex regulatory circuitries. These small RNAs, to
exert their function, are assembled in the functional RNA-induced silencing
complexes (RISCs), where a member of Argonaute (Ago) family of
proteins, Ago1-4, provides a unique platform for target recognition and
gene silencing. Alteration of miRNAs levels and functional activity may
affect proliferation, differentiation and genetic stability of hematopoietic
stem/progenitor cells (HPCs), resulting in myeloproliferative disorders
and leukaemia. Methods. By using myeloid cell lines and prima
Retinoic Acid strongly sensitizes Acute Myeloid Leukemia cells to ER stress
No full textAcute myeloid leukemia (AML) is caused by the blockade of hematopoietic myeloid precursors at different stages of differentiation. A subtype of AML, acute promyelocytic leukemia (APL), is a paradigm of differentiation therapy since all-trans-retinoic acid (ATRA)-based treatments are able to induce leukemic blast terminal differentiation, leading to clinical remission in the majority of APL patients. However, ATRA can lead to systemic toxicity and relapses after initial remission followed by resistance. Furthermore APL accounts for about 10-15% of AML cases and non-APL AML respond only very slightly to ATRA. Thus the search for a strategy to further sensitize AML cells to ATRA is highly needed. Retinoic acid induces differentiation of APL blasts to granulocytes, cells characterized by accumulation of secretory granules containing peptides assembled in the ER. Generally, increased protein folding demand in the ER activates a series of intracellular signal transduction pathways, the unfolded protein response (UPR). The UPR intervenes in reliving ER stress, but if such stress is too strong or prolonged it triggers pro-apoptotic pathways. We set out to investigate if the UPR plays a role in RA-dependent APL differentiation and possibly to exploit RA-induced differentiation to sensitize APL and non-APL AML cells to ER stress.
We found that RA-triggered differentiation deeply altered APL cells sensitivity to ER stress. Indeed doses of tunicamycin or thapsigarging that did not adversely affect proliferating cells resulted in proliferation arrest, cell death and increased differentiation of RA stimulated APL and non-APL cell lines and, most importantly, of human primary leukemic blasts. We show that CHOP is strongly up-regulated upon induction of ER stress in RA-treated APL cells and its down-regulation by shRNA partially restored resistance. Our work suggests that modulation of the UPR in combination with RA based differentiation therapy could be an interesting strategy to target AML cells
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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