GATA family transcriptional factors: emerging suspects in hematologic disorders

Previous research indicated students’ difficulties in acquiring academic reading and writing literacies. Achieving language proficiency expected in higher education often requires hard work from students. Their problems with reading and writing academic texts also presents a challenge for university teachers, who are expected to support students in their academic language development. Our research project aims at exploring how text-based conversations can be used to develop students' understanding of the conventions in academic texts, as well as students’ ability to examine these texts critically.Students’ need for continuous support, related to the educational content, has been discussed before (e.g. Lea & Street, 1998; Monroe, 2003). University teachers, regardless of their subjects or disciplines, can support students’ reading and writing development in a variety of ways (e.g. Lillis & Scott, 2007; Wingate, 2011). Our point of departure is in socio-culturally oriented research on academic writing (e.g. Lea & Street, 1998; Blåsjö, 2004). For this investigation of text-based conversations, however, we also use more text-oriented and genre-based approaches (e.g. Hyland, 2004; Bazerman, Bonini & Figueiredo, 2009).Our project is based on a qualitative study of students' conversations on a scientific text included in their course. The text-based conversations were conducted during a three-hour session, in which the first part included a joint teacher-led discussion between the students and the teacher. This discussion was based on issues focusing some fundamental aspects of a text and its context: what is the problem and purpose of the study, what methods are used and for whom is this article written. The second half of the session was devoted to group discussions, where the task was to examine critically the qualities of the text based on a number of typical features in scientific texts, such as clarity, transparency, independency of context, text structure, and validity claims. The purpose of the assignment was for students to engage in a close reading of the text. These text-based conversations were recorded in several student groups. The recorded material was subsequently transcribed and analysed.We identified three themes relevant to the students’ comprehension of the academic text discussed: the text's usability, the text's reliability, and students' attitudes towards the text and the researchers. The results highlight the teacher’s role in supporting students' reading and writing. Furthermore, the study indicates that students need knowledge about researchers’ working conditions and their writing to understand why academic texts look as they do. In this talk, we focus on the critical potential of text-based conversations as a tool for students’ reading and writing development.References:Bazerman, C., Bonini, A. & Figueiredo, D.D.C. (Eds.). (2009). Genre in a changing world. Fort Collins, Colorado: WAC Clearinghouse.Blåsjö, M. (2004). Studenters skrivande i två kunskapsbyggande miljöer. Stockholm: Almqvist och Wiksell International.Hyland, K. (2004). Disciplinary Discourse. Social Interactions in Academic writing. Michigan: The University of Michigan Press.Lea, M. R. & Street, B. V. (1998). Student writing in higher education: An academic literacies approach. Studies in Higher Education, 23(2), 157-172.Lillis T. M. & Scott, M. (2007). Defining academic literacies research. Issues of epistemology, ideology and strategy. Journal of Applied linguistics, 4(1), 5-32.Monroe, J. (2003). Writing in the disciplines. Peer Review, 6(1), 5-32.Wingate, U., Andon, N. & Cogo, A. (2011). Embedding academic writing instruction int

H2AX Deficiency is Associated with Erythroid Dysplasia and Compromised Haematopoietic Stem Cell Function

Myelodysplastic syndromes (MDS) are clonal disorders of haematopoiesis characterised by dysplastic changes of major myeloid cell lines. However, the mechanisms underlying these dysplastic changes are poorly understood. Here, we used a genetically modified mouse model and human patient data to examine the physiological roles of H2AX in haematopoiesis and how the loss of H2AX contributes to dyserythropoiesis in MDS. H2AX knockout mice showed cell-autonomous anaemia and erythroid dysplasia, mimicking dyserythropoiesis in MDS. Also, dyserythropoiesis was increased in MDS patients with the deletion of chromosome 11q23, where H2AX is located. Although loss of H2AX did not affect the early stage of terminal erythropoiesis, enucleation was decreased. H2AX deficiency also led to the loss of quiescence of hematopoietic stem and progenitor cells, which dramatically compromised their bone marrow engraftment. These results reveal important roles of H2AX in late-stage terminal erythropoiesis and hematopoietic stem cell function

KRAS mutation in secondary malignant histiocytosis arising from low grade follicular lymphoma

Abstract Background Transformation of follicular lymphoma most typically occurs as diffuse large B-cell lymphoma, however other forms of transformation such as classic Hodgkin lymphoma and lymphoblastic transformation can occur. Secondary malignant histiocytosis also represents a rare form of transformation, which is thought to occur due to a process of transdifferentiation whereby the lymphoma cells exhibit lineage plasticity and lose all evidence of B-cell phenotype and instead acquire the phenotype of a histiocytic neoplasm. Little is known about the underlying genetic alterations that occur during this unusual process. Comparative genetic analysis of pre- and post-transformation/transdifferentiation would be one tool by which we could better understand how this phenomenon occurs. Case presentation Here we report the clinical, immunophenotypic and genetic features of a rare case of secondary malignant histiocytosis, Langerhans cell-type (Langerhans cell sarcoma) arising from a previous low grade follicular lymphoma. FISH analysis confirmed the presence of IgH/BCL2 rearrangement in both the low grade follicular lymphoma (FL) and transformed Langerhans cells sarcoma (LCS) samples, demonstrating a clonal relationship. Comparative whole exome sequencing was then performed, which identified a KRAS p.G13D mutation in the LCS that was not present in the FL. Conclusions This report highlights genetic alterations, in particular an acquired somatic KRAS mutation, that may occur during transdifferentiation, with additional significance of KRAS mutation as a possible therapeutic target in cases which otherwise would have limited treatment options.https://deepblue.lib.umich.edu/bitstream/2027.42/145736/1/13000_2018_Article_758.pd

Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition

Myeloid neoplasms with germline predisposition have recently been added as distinct provisional entities in the 2017 revision of the World Health Organization’s classification of tumors of hematopoietic and lymphatic tissue. Individuals with germline predisposition have increased risk of developing myeloid neoplasms—mainly acute myeloid leukemia and myelodysplastic syndrome. Although the incidence of myeloid neoplasms with germline predisposition remains poorly defined, these cases provide unique and important insights into the biology and molecular mechanisms of myeloid neoplasms. Knowledge of the regulation of the germline genes and their interactions with other genes, proteins, and the environment, the penetrance and clinical presentation of inherited mutations, and the longitudinal dynamics during the process of disease progression offer models and tools that can further our understanding of myeloid neoplasms. This knowledge will eventually translate to improved disease sub-classification, risk assessment, and development of more effective therapy. In this review, we will use examples of these disorders to illustrate the key molecular pathways of myeloid neoplasms

miR299a-5p promotes renal fibrosis by suppressing the antifibrotic actions of follistatin

Abstract Caveolin-1 (cav-1), an integral protein of the membrane microdomains caveolae, is required for synthesis of matrix proteins by glomerular mesangial cells (MC). Previously, we demonstrated that the antifibrotic protein follistatin (FST) is transcriptionally upregulated in cav-1 knockout MC and that its administration is protective against renal fibrosis. Here, we screened cav-1 wild-type and knockout MC for FST-targeting microRNAs in order to identity novel antifibrotic therapeutic targets. We identified that miR299a-5p was significantly suppressed in cav-1 knockout MC, and this was associated with stabilization of the FST 3′UTR. Overexpression and inhibition studies confirmed the role of miR299a-5p in regulating FST expression. Furthermore, the profibrotic cytokine TGFβ1 was found to stimulate the expression of miR299a-5p and, in turn, downregulate FST. Through inhibition of FST, miR299a-5p overexpression augmented, while miR299a-5p inhibition diminished TGFβ1 profibrotic responses, whereas miR299a-5p overexpression re-enabled cav-1 knockout MC to respond to TGFβ1. In vivo, miR299a-5p was upregulated in the kidneys of mice with chronic kidney disease (CKD). miR299a-5p inhibition protected these mice against renal fibrosis and CKD severity. Our data demonstrate that miR299a-5p is an important post-transcriptional regulator of FST, with its upregulation an important pathogenic contributor to renal fibrosis. Thus, miR299a-5p inhibition offers a potential novel therapeutic approach for CKD

Rare myeloid sarcoma with KMT2A (MLL)-ELL fusion presenting as a vaginal wall mass

BACKGROUND: Myeloid sarcoma (MS) is a rare neoplasm of immature myeloid precursors that form tumor mass outside the bone marrow. The diagnosis of de novo MS can be challenging, particularly in patients with no prior history of hematologic malignancies or when MS involves unusual anatomic sites. CASE PRESENTATION: The patient was a 53-year-old woman with a history of uterine fibroids and vaginal bleeding for many years who presented with a vaginal wall mass. The tumor had histologic and phenotypic features of histiocytic sarcoma, however, overlapping with a possible extramedullary MS. Using a comprehensive genomic profiling, we were able to identify recurrent chromosomal aberrations associated with MS including a rare KMT2A-ELL fusion, losses of chromosomes 1p, 9, 10, 15, 18, and gain of chromosome 1q and mutations in FLT3 and PTPN11, and achived the final diagnosis of a de novo MS. The patient received standard treatment for acute myeloid leukemia regimen with stem cell transplantation and achieved complete remission. CONCLUSION: Our case illustrates the clinical utility of comprehensive genomic profiling in assisting the diagnosis or differential diagnosis of challenging MS or histiocytic sarcoma cases, and in providing important information in tumor biology for appropriate clinical management