Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Myeloid neoplasms encompass a very heterogeneous family of diseases characterized by the failure of the molecular mechanisms that ensure a balanced equilibrium between hematopoietic stem cells (HSCs) self-renewal and the proper production of differentiated cells. The origin of the driver mutations leading to preleukemia can be traced back to HSC/progenitor cells. Many properties typical to normal HSCs are exploited by leukemic stem cells (LSCs) to their advantage, leading to the emergence of a clonal population that can eventually progress to leukemia with variable latency and evolution. In fact, different subclones might in turn develop from the original malignant clone through accumulation of additional mutations, increasing their competitive fitness. This process ultimately leads to a complex cancer architecture where a mosaic of cellular clones—each carrying a unique set of mutations—coexists. The repertoire of genes whose mutations contribute to the progression toward leukemogenesis is broad. It encompasses genes involved in different cellular processes, including transcriptional regulation, epigenetics (DNA and histones modifications), DNA damage signaling and repair, chromosome segregation and replication (cohesin complex), RNA splicing, and signal transduction. Among these many players, transcription factors, RNA splicing proteins, and deubiquitinating enzymes are emerging as potential targets for therapeutic intervention

Deficiency of ribosomal protein S26, which is mutated in a subset of patients with Diamond Blackfan anemia, impairs erythroid differentiation

Introduction: Diamond Blackfan anemia (DBA) is a rare congenital disease characterized by defective maturation of the erythroid progenitors in the bone marrow, for which treatment involves steroids, chronic transfusions, or hematopoietic stem cells transplantation. Diamond Blackfan anemia is caused by defective ribosome biogenesis due to heterozygous pathogenic variants in one of 19 ribosomal protein (RP) genes. The decreased number of functional ribosomes leads to the activation of pro-apoptotic pathways and to the reduced translation of key genes for erythropoiesis.Results and discussion: Here we characterized the phenotype of RPS26-deficiency in a cell line derived from human umbilical cord blood erythroid progenitors (HUDEP-1 cells). This model recapitulates cellular hallmarks of Diamond Blackfan anemia including: imbalanced production of ribosomal RNAs, upregulation of pro-apoptotic genes and reduced viability, and shows increased levels of intracellular calcium. Evaluation of the expression of erythroid markers revealed the impairment of erythroid differentiation in RPS26-silenced cells compared to control cells.Conclusions: In conclusion, for the first time we assessed the effect of RPS26 deficiency in a human erythroid progenitor cell line and demonstrated that these cells can be used as a scalable model system to study aspects of DBA pathophysiology that have been refractory to detailed investigation because of the paucity of specific cell types affected in this disorder

The Coup-TFII orphan nuclear receptor is an activator of the γ-globin gene

The human fetal γ-globin gene is repressed in the adult stage through complex regulatory mechanisms involving transcription factors and epigenetic modifiers. Reversing γ-globin repression, or maintaining its expression by manipulating regulatory mechanisms, has become a major clinical goal in the treatment of β-hemoglobinopathies. Here, we identify the orphan nuclear receptor Coup-TFII (NR2F2/ARP-1) as an embryonic/fetal stage activator of γ-globin expression. We show that Coup-TFII is expressed in early erythropoiesis of yolk sac origin, together with embryonic/fetal globins. When overexpressed in adult cells (including peripheral blood cells from human healthy donors and β039 thalassemic patients) Coup-TFII activates the embryonic/fetal globins genes, overcoming the repression imposed by the adult erythroid environment. Conversely, the knock-out of Coup-TFII increases the β/γ+β globin ratio. Molecular analysis indicates that Coup-TFII binds in vivo to the β-locus and contributes to its conformation. Overall, our data identify Coup-TFII as a specific activator of the γ-globin gene

A Journey Into the Unknown: PhD Students in a European Training Network on Age-related Changes in Hematopoiesis Conduct Their Project During a Global Pandemic

3 p.-1 fig.This project has received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement no. 813091 (ARCH, age-related changes in hematopoiesis).Peer reviewe

A Journey Into the Unknown: PhD Students in a European Training Network on Age-related Changes in Hematopoiesis Conduct Their Project During a Global Pandemic

The age-related changes in hematopoiesis (ARCH) project is part of the Innovative Training Network (ITN) of the Marie-Sklodowska Curie Actions (MSCA) program, which provides doctorate training of excellence based on the exchange of ideas and competencies from the academic and private sectors.1 The ARCH project intends to outline hematopoietic stem cell (HSC) alterations with aging, how hematopoietic cell individuality is controlled at the transcriptional and epigenetic levels in normal hematopoiesis and in leukemias, and understand the crosstalk between intrinsic and extrinsic indications that support the proliferation of preleukemic and leukemic cells within the hematopoietic niche. We are 15 PhD students funded by this network, based around Europe, and our common aim is to understand functional changes in the hematopoietic system with age, how these changes link to the development of age-associated diseases and in parallel work towards the development of new treatments.2 Our projects kicked off just when the severe acute respiratory coronavirus-2 (SARS-CoV-2) emerged. Two and a half years later, SARS-CoV-2 continues to infect millions of people and has taken the lives of at least 6 million people worldwide.3 The COVID-19 outbreak brought along social isolation and feelings of uncertainty to everyone around the world, including doctorate students.4,5 Ironically, our projects have been more relevant than ever, as the pandemic has highlighted the important relationship between age-related changes in hematopoiesis and disease severity. Below, we aim to discuss the timeline of the ARCH project throughout the pandemic and how we managed to courageously pull through the hardships of doing research during a global pandemic within different settings (academia/institutes and industry). We provide recommendations to future PhD students on how to manage their PhD projects during global emergencies.The age-related changes in hematopoiesis (ARCH) project is part of the Innovative Training Network (ITN) of the Marie-Sklodowska Curie Actions (MSCA) program, which provides doctorate training of excellence based on the exchange of ideas and competencies from the academic and private sectors.1 The ARCH project intends to outline hematopoietic stem cell (HSC) alterations with aging, how hematopoietic cell individuality is controlled at the transcriptional and epigenetic levels in normal hematopoiesis and in leukemias, and understand the crosstalk between intrinsic and extrinsic indications that support the proliferation of preleukemic and leukemic cells within the hematopoietic niche. We are 15 PhD students funded by this network, based around Europe, and our common aim is to understand functional changes in the hematopoietic system with age, how these changes link to the development of age-associated diseases and in parallel work towards the development of new treatments.2 Our projects kicked off just when the severe acute respiratory coronavirus-2 (SARS-CoV-2) emerged. Two and a half years later, SARS-CoV-2 continues to infect millions of people and has taken the lives of at least 6 million people worldwide.3 The COVID-19 outbreak brought along social isolation and feelings of uncertainty to everyone around the world, including doctorate students.4,5 Ironically, our projects have been more relevant than ever, as the pandemic has highlighted the important relationship between age-related changes in hematopoiesis and disease severity. Below, we aim to discuss the timeline of the ARCH project throughout the pandemic and how we managed to courageously pull through the hardships of doing research during a global pandemic within different settings (academia/institutes and industry). We provide recommendations to future PhD students on how to manage their PhD projects during global emergencies