scholarly journals Uncoding the genetic heterogeneity of myelodysplastic syndrome

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 447-452 ◽  
Author(s):  
R. Coleman Lindsley
Keyword(s):  
Myelodysplastic Syndrome ◽  
Germ Line ◽  
Cytotoxic Chemotherapy ◽  
Driver Mutations ◽  
Disease Pathogenesis ◽  
Genetic Process ◽  
Core Set ◽  
Abnormal Bone Marrow ◽  
Genomic Studies ◽  
Kinetics Of

Abstract Myelodysplastic syndrome (MDS) is a clinically heterogeneous disease characterized by functional impairment of hematopoiesis and abnormal bone marrow morphology. The type and severity of hematopoietic dysfunction in MDS are highly variable, and the kinetics of disease progression are difficult to predict. Genomic studies have shown that MDS is typically driven by a multistep somatic genetic process affecting a core set of genes. By definition, recurrent MDS driver mutations all drive clonal dominance, although they can have stereotyped positions in the clonal hierarchy or patterns of comutation association and exclusivity. Furthermore, environmental context, such as exposures to cytotoxic chemotherapy or the presence of germ-line predisposition, can influence disease pathogenesis and clinical outcomes. This review will address how an enhanced understanding of MDS genetics may enable refinement of current diagnostic schema, improve understanding of the pathogenesis of therapy-related MDS, and identify germ-line predispositions to development of MDS that are more common than recognized by standard clinical evaluation.

scholarly journals Systematic Review of Recurrent Osteosarcoma Systemic Therapy

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1757
Author(s):  
Ioanna Gazouli ◽  
Anastasios Kyriazoglou ◽  
Ioannis Kotsantis ◽  
Maria Anastasiou ◽  
Anastasios Pantazopoulos ◽  
...  
Keyword(s):  
Clinical Evidence ◽  
Treatment Effectiveness ◽  
Treatment Strategies ◽  
Bone Cancer ◽  
Predictive Biomarkers ◽  
Mtor Inhibitors ◽  
Cytotoxic Chemotherapy ◽  
Driver Mutations ◽  
Preclinical Research ◽  
Primary Bone

Osteosarcoma is the most frequent primary bone cancer, mainly affecting those of young ages. Although surgery combined with cytotoxic chemotherapy has significantly increased the chances of cure, recurrent and refractory disease still impose a tough therapeutic challenge. We performed a systematic literature review of the available clinical evidence, regarding treatment of recurrent and/or refractory osteosarcoma over the last two decades. Among the 72 eligible studies, there were 56 prospective clinical trials, primarily multicentric, single arm, phase I or II and non-randomized. Evaluated treatment strategies included cytotoxic chemotherapy, tyrosine kinase and mTOR inhibitors and other targeted agents, as well as immunotherapy and combinatorial approaches. Unfortunately, most treatments have failed to induce objective responses, albeit some of them may sustain disease control. No driver mutations have been recognized, to serve as effective treatment targets, and predictive biomarkers of potential treatment effectiveness are lacking. Hopefully, ongoing and future clinical and preclinical research will unlock the underlying biologic mechanisms of recurrent and refractory osteosarcoma, expanding the therapeutic choices available to pre-treated osteosarcoma patients.

scholarly journals LncRNA Profiling Reveals That the Deregulation of H19, WT1-AS, TCL6, and LEF1-AS1 Is Associated with Higher-Risk Myelodysplastic Syndrome

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2726
Author(s):  
Katarina Szikszai ◽  
Zdenek Krejcik ◽  
Jiri Klema ◽  
Nikoleta Loudova ◽  
Andrea Hrustincova ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Bone Marrow Cells ◽  
Expression Profiles ◽  
Chromatin Modification ◽  
Adverse Outcomes ◽  
Disease Pathogenesis ◽  
Protein Coding ◽  
Hematopoietic Stem ◽  
Risk Of Progression ◽  
Patient Prognosis

Background: myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder with an incompletely known pathogenesis. Long noncoding RNAs (lncRNAs) play multiple roles in hematopoiesis and represent a new class of biomarkers and therapeutic targets, but information on their roles in MDS is limited. Aims: here, we aimed to characterize lncRNAs deregulated in MDS that may function in disease pathogenesis. In particular, we focused on the identification of lncRNAs that could serve as novel potential biomarkers of adverse outcomes in MDS. Methods: we performed microarray expression profiling of lncRNAs and protein-coding genes (PCGs) in the CD34+ bone marrow cells of MDS patients. Expression profiles were analyzed in relation to different aspects of the disease (i.e., diagnosis, disease subtypes, cytogenetic and mutational aberrations, and risk of progression). LncRNA-PCG networks were constructed to link deregulated lncRNAs with regulatory mechanisms associated with MDS. Results: we found several lncRNAs strongly associated with disease pathogenesis (e.g., H19, WT1-AS, TCL6, LEF1-AS1, EPB41L4A-AS1, PVT1, GAS5, and ZFAS1). Of these, downregulation of LEF1-AS1 and TCL6 and upregulation of H19 and WT1-AS were associated with adverse outcomes in MDS patients. Multivariate analysis revealed that the predominant variables predictive of survival are blast count, H19 level, and TP53 mutation. Coexpression network data suggested that prognosis-related lncRNAs are predominantly related to cell adhesion and differentiation processes (H19 and WT1-AS) and mechanisms such as chromatin modification, cytokine response, and cell proliferation and death (LEF1-AS1 and TCL6). In addition, we observed that transcriptional regulation in the H19/IGF2 region is disrupted in higher-risk MDS, and discordant expression in this locus is associated with worse outcomes. Conclusions: we identified specific lncRNAs contributing to MDS pathogenesis and proposed cellular processes associated with these transcripts. Of the lncRNAs associated with patient prognosis, the level of H19 transcript might serve as a robust marker comparable to the clinical variables currently used for patient stratification.

scholarly journals BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice

Blood ◽  
1995 ◽  
Vol 86 (12) ◽  
pp. 4603-4611 ◽  
Author(s):  
JW Voncken ◽  
V Kaartinen ◽  
PK Pattengale ◽  
WT Germeraad ◽  
J Groffen ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Germ Line ◽  
Latency Period ◽  
Chronic Phase ◽  
Transgenic Animals ◽  
Hematopoietic Tissue ◽  
Long Latency ◽  
Short Period ◽  
Kinetics Of ◽  
Overt Disease

DNA constructs encoding BCR/ABL P210 have been introduced into the mouse germ line using microinjection of one-cell fertilized eggs. Kinetics of BCR/ABL P210 expression in transgenic mice were very similar to those of BCR/ABL P190 constructs in transgenic mice. mRNA transcripts were detectable early in embryonic development and also in hematopoietic tissue of adult animals. Expression of BCR/ABL in peripheral blood preceded development of overt disease. P210 founder and progeny transgenic animals, when becoming ill, developed leukemia of B, T-lymphoid, or myeloid origin after a relatively long latency period. In contrast, P190-transgenic mice exclusively developed leukemia of B-cell origin, with a relatively short period of latency. The observed dissimilarities are most likely due to intrinsically different properties of the P190 and P210 oncoproteins and may also involve sequences that control transgene expression. The delayed progression of BCR/ABL P210-associated disease in the transgenic mice is consistent with the apparent indolence of human chronic myeloid leukemia during the chronic phase. We conclude that, in transgenic models, comparable expression of BCR/ABL P210 and BCR/ABL P190 results in clinically distinct conditions.

scholarly journals Driver Mutations in Leukemia Promote Disease Pathogenesis through a Combination of Cell-Autonomous and Niche Modulation

2020 ◽  
Vol 15 (1) ◽  
pp. 95-109 ◽  
Author(s):  
Baskar Ramdas ◽  
Raghuveer Singh Mali ◽  
Lakshmi Reddy Palam ◽  
Ruchi Pandey ◽  
Zhigang Cai ◽  
...  
Keyword(s):  
Driver Mutations ◽  
Disease Pathogenesis

Involvement of ERK, p38 and NFκB Signalling in the Maturation Defects of Monocyte Derived Dendritic Cells in Patients with Myelodysplastic Syndrome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4891-4891
Author(s):  
Ilina Micheva ◽  
Panos Ziros ◽  
Lorna Pherson ◽  
Nikolaos Giannakoulas ◽  
Argiris Symeonidis ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Myelodysplastic Syndrome ◽  
Nuclear Translocation ◽  
Binding Activity ◽  
Dc Functions ◽  
Migratory Capacity ◽  
Erk Phosphorylation ◽  
Tnf Α ◽  
Antigen Presenting ◽  
Kinetics Of

Abstract Dendritic cells (DC) are professional antigen-presenting cells involved in the initiation of T-cell dependent immune responses. The maturation process is central for the DC and enables them to perform different functions sequentially. We have recently demonstrated that in patients with myelodysplastic syndrome (MDS) monocyte-derived DC (MoDC) exhibit some phenotypic and functional abnormalities with a maturation failure toward TNF-α but not LPS. However, the mechanisms underlying the differential response to those stimuli have not yet been clarified. In the present study three different signalling pathways, ERK, p38K and NFκB, known to be implicated in MoDC maturation, were examined on TNF-α or LPS stimulated MoDC from 7 patients with MDS and 5 healthy controls. We also analyzed DC functions such as migration and cytokine secretion controlled by the coordinated actions of those signal transduction pathways. In agreement with our previous report stimulation of MoDC with LPS but not with TNF-α induced up-regulation of CD83, CD40, CD80 expression and allostimulatory activity of MoDC in MDS patients. Activation of MDS MoDC with LPS but not TNF-α was accompanied by nuclear translocation of NFκB. Accordingly, in 6/7 patients the NFκB binding activity following stimulation with TNF-α for 48 hours was extremely low, whereas LPS stimulated NFκB activity in MDS MoDC, although at lower levels compared to control MoDC. This was accompanied by lower than control migratory capacity (0.73±0.6 vs.3.75±0.6 x 103) and lack of IL-12p70 secretion by LPS-stimulated MoDC from patients. Interestingly, in one patient with similar to control NFκB activity the migration and IL-12p70 production were comparable to the controls. TNF-α stimulation resulted in MoDC with migratory capacity but no IL-12p70 production even after 48 hours stimulation in both patients and controls. However, the migration of MDS MoDC toward CCL21 was significantly lower (0.55±0.5 vs.2.4±1.7 x 103). Both TNF-α and LPS induced phosphorylation of p38 and ERK after 48 hours stimulation at similar levels in MoDC from controls, whereas in MDS MoDC the pattern was heterogeneous with predominant activation of ERK over p38K. The kinetics of p38K and ERK phosphorylation differed in TNF-α activated MDS MoDC. Rapid phosphorylation of p38K and ERK 30 min after stimulation was followed by loss of p38 activity and persistent activation of ERK after 48 hours. Our results provide strong evidence that NFκB is responsible for the differences in the phenotype and allostimulatory capacity of MDS MoDC after TNF-α and LPS stimulation, since LPS induced NFkB activity, although at lower levels compared to control. The low NFκB activity in MDS MoDC shows that the maturation failure of MDS MoDC, including functions such as migration and IL-12p70 secretion, is NFκB dependent. In addition, predominant activation of ERK pathway is probably also involved in the negative regulation of these MDS MoDC functions.

scholarly journals Insights into Mechanisms of Tumorigenesis in Neuroendocrine Neoplasms

2021 ◽  
Vol 22 (19) ◽  
pp. 10328
Author(s):  
Lorenza Pastorino ◽  
Federica Grillo ◽  
Manuela Albertelli ◽  
Paola Ghiorzo ◽  
William Bruno
Keyword(s):  
Animal Models ◽  
Biological Effects ◽  
Basic Research ◽  
Driver Mutations ◽  
Neuroendocrine Neoplasm ◽  
Neuroendocrine Neoplasms ◽  
Molecular Events ◽  
Depth Study ◽  
Genomic Studies ◽  
The Many

Genomic studies have identified some of the most relevant genetic players in Neuroendocrine Neoplasm (NEN) tumorigenesis. However, we are still far from being able to draw a model that encompasses their heterogeneity, elucidates the different biological effects consequent to the identified molecular events, or incorporates extensive knowledge of molecular biomarkers and therapeutic targets. Here, we reviewed recent insights in NEN tumorigenesis from selected basic research studies on animal models, highlighting novel players in the intergenic cooperation and peculiar mechanisms including splicing dysregulation, chromatin stability, or cell dedifferentiation. Furthermore, models of tumorigenesis based on composite interactions other than a linear progression of events are proposed, exemplified by the involvement in NEN tumorigenesis of genes regulating complex functions, such as MEN1 or DAXX. Although limited by interspecies differences, animal models have proved helpful for the more in-depth study of every facet of tumorigenesis, showing that the identification of driver mutations is only one of the many necessary steps and that other mechanisms are worth investigating.

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