Hematopoietic Research Articles

CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma.

Lymphoma is the most common hematological malignancy and is among the 10 most prevalent cancers worldwide. Although survival has been improved by modern immunochemotherapeutic regimens, there remains a significant need for novel targeted agents to treat both B-cell and T-cell malignancies. Cytidine triphosphate synthase 1 (CTPS1), which catalyzes the rate-limiting step in pyrimidine synthesis, plays an essential and nonredundant role in B-cell and T-cell proliferation but is complemented by the homologous CTPS2 isoform outside the hemopoietic system. This report describes the identification and characterization of CTPS1 as a novel target in B- and T-cell cancers. A series of small molecules have been developed which show potent and highly selective inhibition of CTPS1. Site-directed mutagenesis studies identified the adenosine triphosphate pocket of CTPS1 as the binding site for this small molecule series. In preclinical studies, a potent and highly selective small molecule inhibitor of CTPS1 blocked the in vitro proliferation of human neoplastic cells, showing the highest potency against lymphoid neoplasms. Importantly, pharmacological CTPS1 inhibition induced cell death by apoptosis in the majority of lymphoid cell lines tested, thus demonstrating a cytotoxic mechanism of action. Selective CTPS1 inhibition also inhibited the growth of neoplastic human B- and T- cells in vivo. These findings identify CTPS1 as a novel therapeutic target in lymphoid malignancy. A compound from this series is in phase 1/2 clinical studies for the treatment of relapsed/refractory B- and T-cell lymphoma (NCT05463263).

Dietary beauvericin and enniatin B exposure cause different adverse health effects in farmed Atlantic salmon.

The extensive use of plant ingredients in novel aquafeeds have introduced mycotoxins to the farming of seafood. The emerging enniatin B (ENNB) and beauvericin (BEA) mycotoxins have been found in the novel aquafeeds and farmed fish. Little is known about the potential toxicity of ENNs and BEA in farmed fish and their feed-to-organ transfer. Atlantic salmon (Salmo salar) pre-smolt (75.3±8.10g) were fed four graded levels of spiked chemical pure ENNB or BEA feeds for three months, in triplicate tanks. Organismal adverse health end-point assessment included intestinal function (protein digestibility), disturbed hematology (red blood cell formation), bone formation (spinal deformity), overall energy use (feed utilization), and lipid oxidative status (vitamin E). Both dietary BEA and ENNB had a low (<∼0.01%) transfer to organs (kidney>liver>brain>muscle), with a higher transfer for ENNB compared to BEA. BEA caused a growth reduction combined with a decreased protein digestion and feed conversion rate- ENNB caused a stunted growth, unrelated to feed utilization capacity. In addition, ENNB caused anemia while BEA gave an oxidative stress response. Lower bench-mark dose regression assessment showed that high background levels of ENNB in commercial salmon feed could pose a risk for animal health, but not in the case of BEA.

The Effect of Giving Mung Bean Juice to Increasing Hemoglobin Levels in Pregnant Women at the Sungai Kapih Health Center in Samarinda

Nutritional anemia is a health problem that contributes to the high maternal mortality rate. How to treat anemia with Fe tablets and increase intake of food sources of Fe. The purpose of this study was to determine the effect of green bean juice on increasing hemoglobin levels in pregnant women. The research method uses a quasi experiment with a two group pretest - posttest design. The total sample is 24 respondents. The sampling technique uses accidental sampling. Independent sample t-test results (pvalue = 0.002). There is a difference in the increase in hemoglobin levels before and after the intervention. Discussion: Green beans have an iron content of 6.74 mg per 100 g of green beans which are useful in the formation of red blood cells. Giving green bean juice is more effective for increasing hemoglobin levels of pregnant women.

Ex vivo reprogramming of human hematopoietic stem cells is accompanied by increased transcripts of genes regulating metabolic integrity

The regenerative potential of human hematopoietic stem cells (HSCs) is functionally defined by their ability to provide life-long blood cell production and to repopulate myeloablated allogeneic transplant recipients. The expansion of HSC numbers is dependent not only on HSC divisions but also on a coordinated adaptation of HSCs to metabolic stress. These variables are especially critical during the ex vivo culture of HSCs with cytokine combinations, which frequently results in HSC exhaustion. We have previously reported that human CD34+ hematopoietic stem and progenitor cells (HSPCs) can be efficiently reprogrammed ex vivo and that the number of phenotypic HSCs with long-term repopulation capacity is expanded in the presence of a combination of cytokines and an epigenetic modifier. Here, we present evidence that ex vivo HSC reprogramming and maintenance is accompanied by increased transcripts of genes regulating metabolic integrity, including SIRT1 and SIRT3.

A single approach to targeting transferrin receptor 2 corrects iron and erythropoietic defects in murine models of anemia of inflammation and chronic kidney disease

Anemia is a common complication of systemic inflammation. Proinflammatory cytokines both decrease erythroblast sensitivity to erythropoietin (EPO) and increase the levels of the hepatic hormone hepcidin, sequestering iron in stores and causing functional iron deficiency. Anemia of chronic kidney disease (CKD) is a peculiar form of anemia of inflammation, characterized by impaired EPO production paralleling progressive kidney damage. Traditional therapy based on increased EPO (often in combination with iron) may have off-target effects due to EPO interaction with its non-erythroid receptors. Transferrin Receptor 2 (Tfr2) is a mediator of the iron-erythropoiesis crosstalk. Its deletion in the liver hampers hepcidin production, increasing iron absorption, whereas its deletion in the hematopoietic compartment increases erythroid EPO sensitivity and red blood cell production. Here, we show that selective hematopoietic Tfr2 deletion ameliorates anemia in mice with sterile inflammation in the presence of normal kidney function, promoting EPO responsiveness and erythropoiesis without increasing serum EPO levels. In mice with CKD, characterized by absolute rather than functional iron deficiency, Tfr2 hematopoietic deletion had a similar effect on erythropoiesis but anemia improvement was transient because of limited iron availability. Also, increasing iron levels by downregulating only hepatic Tfr2 had a minor effect on anemia. However, simultaneous deletion of hematopoietic and hepatic Tfr2, stimulating erythropoiesis and increased iron supply, was sufficient to ameliorate anemia for the entire protocol. Thus, our results suggest that combined targeting of hematopoietic and hepatic Tfr2 may be a therapeutic option to balance erythropoiesis stimulation and iron increase, without affecting EPO levels.

HBB Gene Mutations and Their Pathological Impacts on HbE/β-Thalassaemia in Kuala Terengganu, Malaysia.

β-thalassaemia is a disorder caused by mutations in the β-globin gene, leading to defective production of haemoglobins (Hb) and red blood cells (RBCs). It is characterised by anaemia, ineffective erythropoiesis, and iron overload. Patients with severe β-thalassaemia require lifelong blood transfusions. Haemoglobin E beta-thalassaemia (HbE/β-thalassaemia) is a severe form of β-thalassaemia in Asian countries. More than 200 alleles have been recognised in the β-globin region. Different geographical regions show different frequencies of allelic characteristics. In this study, the spectrum of β-thalassaemia (β-thal) alleles and their correlation with iron overload, in HbE/β-thalassaemia patients, β-thalassaemia trait, and HbE trait were studied. Blood samples (n = 260) were collected from 65 β-thalassaemia patients, 65 parents (fathers and/or mothers) and 130 healthy control individuals. Haematological analyses, iron profiles, and serum hepcidin levels were examined for all participants. DNA was extracted from patients' and their parents' blood samples, then subjected to PCR amplification. Multiplex amplification refractory mutation system PCR (MARMS-PCR) was conducted for eighteen primers to detect the mutations. There was severe anaemia present in HbE/β-thalassaemia patients compared to their parents and healthy controls. The ferritin and iron levels were significantly increased in patients compared to their parents and healthy controls (p = 0.001). Two common mutations were detected among the patient group and three mutations were detected among their parents, in addition to seven novel mutations in HbE/β-thalassaemia patients (explained in results). Some mutations were associated with severe anaemia in β-thalassaemia patients. The detection of mutations is a prognostic marker, and could enhance the appropriate management protocols and improve the haematological and biochemical statuses of β-thalassaemia patients.

ESTIMATION OF TOTAL LEUCOCYTE COUNT AND ERYTHROCYTE SEDIMENTATION RATE IN Channa punctatus (BLOCH.) UNDER TOXIC STRESS OF POTTERY CHEMICALS

The pottery and ceramic industry release toxic heavy metals during preparation and other steps which in turn go to environment and finally to aquatic ecosystem through leaching and runoff water. In the view of above facts it is mandatory to explore this non target effect of ceramic industry for aquatic ecosystem. A dye is a coloured material that chemically attaches to the substrate it is applied on. Dyes are distinguished from pigments by the fact that they do not chemically attach to the substrate they colour. In most cases, the dye is administered in an aqueous solution. Keeping these points in view, the present study is undertaken to assess impact of pottery industry chemical tin oxide on total leucocyte count and erythrocyte sedimentation rate of Channa punctatus (Bloch.). The TLC and ESR have been found to be increased after treatment due to hematotoxic effect of pottery chemicals and adverse effect on hemopoietic system of fish. Keywords: Channa punctatus (Bloch.), Pottery chemicals, Pottery industry, TLC, ESR

Overview of hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is the intravenous administration of hematopoietic stem cells (HSC) to restore blood cell production in individuals whose bone marrow or immune system is damaged or dysfunctional. This approach has been utilized to treat a variety of malignant and nonmalignant disorders for the past half-century. HSCT is performed in two ways, autologous and allogeneic. In the clinic, the type of stem cell transplant is decided for the patient according to the patient's diagnosis. Both types of transplantation have advantages as well as disadvantages. Knowing and managing the HSCT process well affects the success of the transplant. Knowing the complications that may occur after transplantation will facilitate the treatment process of the patient. In this short review, the HSCT process has been tried to be explained with general titles.

AURKB Geni miR-34a-5p ve let-7b-5p Tarafından Hedeflendiğinden AML Hücre Proliferasyonunda Rol Oynar mı?

Objective: The production of normal blood cells in the bone marrow is interrupted in AML, which is characterized by the proliferation and accumulation of leukemic blasts. Therefore, patients experience anemia and thrombocytopenia. When gene expression of Aurora kinases, which is reported to be highly expressed in AML, decreases, it may be possible to alleviate the clinical findings in AML. In this study, it was aimed to examine the relationship of AURKB with important miRNAs that have the potential to regulate gene expression. &#x0D; Method: HL60 and NB4 cells were transfected with important tumor suppressor miRNAs miR-34a-5p and let-7b-5p mimics. Then, its effects on proliferation were examined with WST-8 technique and its effects on AURKB gene expression were examined with qRT-PCR.&#x0D; Results: It was determined that these miRNAs negatively regulated proliferation in both AML cell lines and downregulated the expression level of the Aurora kinase B (AURKB) gene in the miRNA transfected group compared to the control group.&#x0D; Conclusion: In conclusion, it was determined that miR-34a-5p and let-7b-5p could regulate AURKB expression in AML cells. Therefore, it was thought that these miRNAs may have an important potential as a therapeutic biomarker in preventing excessive cell division and poor prognosis in AML.

Development and validation of a method for analyzing the sialylated glycopeptides of recombinant erythropoietin in urine using LC–HRMS

Erythropoietin (EPO) is a glycoprotein hormone that stimulates red blood cell production. It is produced naturally in the body and is used to treat patients with anemia. Recombinant EPO (rEPO) is used illicitly in sports to improve performance by increasing the blood’s capacity to carry oxygen. The World Anti-Doping Agency has therefore prohibited the use of rEPO. In this study, we developed a bottom-up mass spectrometric method for profiling the site-specific N-glycosylation of rEPO. We revealed that intact glycopeptides have a site-specific tetra-sialic glycan structure. Using this structure as an exogenous marker, we developed a method for use in doping studies. The profiling of rEPO N-glycopeptides revealed the presence of tri- and tetra-sialylated N-glycopeptides. By selecting a peptide with a tetra-sialic acid structure as the target, its limit of detection (LOD) was estimated to be < 500 pg/mL. Furthermore, we confirmed the detection of the target rEPO glycopeptide using three other rEPO products. We additionally validated the linearity, carryover, selectivity, matrix effect, LOD, and intraday precision of this method. To the best of our knowledge, this is the first report of a doping analysis using liquid chromatography/mass spectrometry-based detection of the rEPO glycopeptide with a tetra-sialic acid structure in human urine samples.

Roles of focal adhesion proteins in skeleton and diseases.

The skeletal system, which contains bones, joints, tendons, ligaments and other elements, plays a wide variety of roles in body shaping, support and movement, protection of internal organs, production of blood cells and regulation of calcium and phosphate metabolism. The prevalence of skeletal diseases and disorders, such as osteoporosis and bone fracture, osteoarthritis, rheumatoid arthritis, and intervertebral disc degeneration, increases with age, causing pain and loss of mobility and creating a huge social and economic burden globally. Focal adhesions (FAs) are macromolecular assemblies that are composed of the extracellular matrix (ECM), integrins, intracellular cytoskeleton and other proteins, including kindlin, talin, vinculin, paxillin, pinch, Src, focal adhesion kinase (FAK) and integrin-linked protein kinase (ILK) and other proteins. FA acts as a mechanical linkage connecting the ECM and cytoskeleton and plays a key role in mediating cell-environment communications and modulates important processes, such as cell attachment, spreading, migration, differentiation and mechanotransduction, in different cells in skeletal system by impacting distinct outside-in and inside-out signaling pathways. This review aims to integrate the up-to-date knowledge of the roles of FA proteins in the health and disease of skeletal system and focuses on the specific molecular mechanisms and underlying therapeutic targets for skeletal diseases.

Excessive Erythrocytosis Is Not Associated With Altered Iron Homeostasis in Men From the World's Highest City.

Excessive Erythrocytosis Is Not Associated With Altered Iron Homeostasis in Men From the World's Highest City.

Gene Mutation Spectrum among Alpha-Thalassaemia Patients in Northeast Peninsular Malaysia.

(1) Background: Alpha (α)-thalassaemia is a genetic disorder that affects 5% of the world population. Deletional or nondeletional mutations of one or both HBA1 and HBA2 on chromosome 16 will result in reduced production of α-globin chains, a component of haemoglobin (Hb) that is required for the formation of red blood cells (RBCs). This study aimed to determine the prevalence, haematological and molecular characterisations of α-thalassaemia. (2) Method: The parameters were based on full blood count, high-performance liquid chromatography and capillary electrophoresis. The molecular analysis involved gap-polymerase chain reaction (PCR), multiplex amplification refractory mutation system-PCR, multiplex ligation-dependent probe amplification and Sanger sequencing. (3) Results: With a total cohort of 131 patients, the prevalence of α-thalassaemia was 48.9%, leaving the remaining 51.1% with potentially undetected α gene mutations. The following genotypes were detected: -α3.7/αα (15.4%), -α4.2/αα (3.7%), --SEA/αα (7.4%), αCSα/αα (10.3%), αAdanaα/αα (0.7%), αQuong Szeα/αα (1.5%), -α3.7/-α3.7 (0.7%), αCSα/αCSα (0.7%), -α4.2/αCSα (0.7%), -SEA/αCSα (1.5%), -SEA/αQuong Szeα (0.7%), -α3.7/αAdanaα (0.7%), --SEA/-α3.7 (2.2%) and αCSα/αAdanaα (0.7%). Indicators such as Hb (p = 0.022), mean corpuscular volume (p = 0.009), mean corpuscular haemoglobin (p = 0.017), RBC (p = 0.038) and haematocrit (p = 0.058) showed significant changes among patients with deletional mutations, but not between patients with nondeletional mutations. (4) Conclusions: A wide range of haematological parameters was observed among patients, including those with the same genotype. Thus, a combination of molecular technologies and haematological parameters is necessary for the accurate detection of α-globin chain mutations.

Metabolic crosstalk between stromal and malignant cells in the bone marrow niche

Bone marrow is the primary site of blood cell production in adults and serves as the source of osteoblasts and osteoclasts that maintain bone homeostasis. The medullary microenvironment is also involved in malignancy, providing a fertile soil for the growth of blood cancers or solid tumors metastasizing to bone. The cellular composition of the bone marrow is highly complex, consisting of hematopoietic stem and progenitor cells, maturing blood cells, skeletal stem cells, osteoblasts, mesenchymal stromal cells, adipocytes, endothelial cells, lymphatic endothelial cells, perivascular cells, and nerve cells. Intercellular communication at different levels is essential to ensure proper skeletal and hematopoietic tissue function, but it is altered when malignant cells colonize the bone marrow niche. While communication often involves soluble factors such as cytokines, chemokines, and growth factors, as well as their respective cell-surface receptors, cells can also communicate by exchanging metabolic information. In this review, we discuss the importance of metabolic crosstalk between different cells in the bone marrow microenvironment, particularly concerning the malignant setting.

Clinical Treatments of Various Diseases with The Root of Astragalus Membranaceus

Astragalus L., is one of the largest genuses of flowering plants in the Leguminosae family. As annual or perennial herbs, sub shrubs, or shrubs, the plants of Astragalus L. are widely distributed throughout the temperate and arid regions. So far, the genus has been estimated to contain 2000–3000 species and more than 250 taxonomic sections in the world. Astragalus can significantly improve motor and memory impairment following D-galactose induced senescence in mice, which suggests anti-aging effects and possibly a delay in senility of middle-aged mice. The root of A. membranceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao (Radix Astragali) is a precious medicine in TCM, which has the properties of intensifying phagocytosis of reticuloendothelial systems, stimulating pituitary-adrenal cortical activity, and restoring depleted red blood cell formation in bone marrow. Clinically, it is used to treat chronic phlegmatic disorders and general gastrointestinal disturbances including stomach ulcers and diarrhea. It has been used in traditional Chinese medicine (TCM) in the treatment of various renal diseases for over 2000 years and was recorded in Shen Nong’s Materia Medica, which was written in the Han dynasty. Also, it is famed for its antimicrobial, antiperspirant, anti-inflammatory, diuretic and tonic effects. Some plants in the Astragalus genus are well known for their pharmacological properties, particularly hepatoprotective, immunostimulant, and antiviral activities. While, the most common use of this genus is as forage for livestock and wild animals, some plants in this genus have been recognized as being used in foods, medicines, cosmetics, as substitutes for tea or coffee, or as sources of vegetable gums. Saponins, flavonoids, and polysaccharides are believed to be the principle active constituents of Astragalus. This herb possesses tonic, hepatoprotective, diuretic, and expectorant properties and has been shown to exhibit immunomodulating, antihyperglycemic, and antiviral activities, among others. Traditionally, it was used to treat weakness, wounds, anemia, fever, multiple allergies, chronic fatigue, and loss of appetite, uterine bleeding, and uterine prolapse. The plants have also been used for treatment of diabetes, nephritis, leukemia, stomach ulcers, hypertension and chronic bronchitis.

Hacking hematopoiesis - emerging tools for examining variant effects.

Hematopoiesis is a continuous process of blood and immune cell production. It is orchestrated by thousands of gene products that respond to extracellular signals by guiding cell fate decisions to meet the needs of the organism. Although much of our knowledge of this process comes from work in model systems, we have learned a great deal from studies on human genetic variation. Considerable insight has emerged from studies on presumed monogenic blood disorders, which continue to provide key insights into the mechanisms critical for hematopoiesis. Furthermore, the emergence of large-scale biobanks and cohorts has uncovered thousands of genomic loci associated with blood cell traits and diseases. Some of these blood cell trait-associated loci act as modifiers of what were once thought to be monogenic blood diseases. However, most of these loci await functional validation. Here, we discuss the validation bottleneck and emerging methods to more effectively connect variant to function. In particular, we highlight recent innovations in genome editing, which have paved the path forward for high-throughput functional assessment of loci. Finally, we discuss existing barriers to progress, including challenges in manipulating the genomes of primary hematopoietic cells.

Cerebral venous thrombosis in polycythemia rubra vera: a rare case report

Polycythemia rubra vera (PV) is a disease characterised by increased production of red blood cells due to genetic mutation which leads to increase in RBC mass and increased viscocity of blood. Myeloproliferative neoplasms have been implicated in the causation of cerebral venous thrombosis (CVT). Here we presented a 34 year old male who present with headache and diplopia. Fundus examination revealed bilateral papilledema. MRI brain with venogram was done which revealed right transverse and sigmoid sinus thrombosis. Blood investigations revealed polycythemia, elevated RBC counts and hematocrit levels. Peripheral smear showed increased RBC, WBC and platelets. Serum erythropoietin was low. Bone marrow aspiration study revealed hypercellular marrow. Patient tested positive for JAK2 V617F mutation. Patient was treated with anticoagulants, therapeutic phlebotomy and other supportive measures. Here we present a rare case of PV presenting with CVT.

Neuronal nitric oxide synthase is required for erythropoietin stimulated erythropoiesis in mice.

Introduction: Erythropoietin (EPO), produced in the kidney in a hypoxia responsive manner, is required for red blood cell production. In non-erythroid tissue, EPO increases endothelial cell production of nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) that regulates vascular tone to improve oxygen delivery. This contributes to EPO cardioprotective activity in mouse models. Nitric oxide treatment in mice shifts hematopoiesis toward the erythroid lineage, increases red blood cell production and total hemoglobin. In erythroid cells, nitric oxide can also be generated by hydroxyurea metabolism that may contribute to hydroxyurea induction of fetal hemoglobin. We find that during erythroid differentiation, EPO induces neuronal nitric oxide synthase (nNOS) and that neuronal nitric oxide synthase is required for normal erythropoietic response. Methods: Wild type (WT) mice and mice with targeted deletion of nNOS (nNOS-/-) and eNOS (eNOS-/-) were assessed for EPO stimulated erythropoietic response. Bone marrow erythropoietic activity was assessed in culture by EPO dependent erythroid colony assay and in vivo by bone marrow transplantation into recipient WT mice. Contribution of nNOS to EPO stimulated cell proliferation was assessed in EPO dependent erythroid cells and in primary human erythroid progenitor cell cultures. Results: EPO treatment increased hematocrit similarly in WT and eNOS-/- mice and showed a lower increase in hematocrit nNOS-/- mice. Erythroid colony assays from bone marrow cells were comparable in number from wild type, eNOS-/- and nNOS-/- mice at low EPO concentration. Colony number increased at high EPO concentration is seen only in cultures from bone marrow cells of wild type and eNOS-/- mice but not from nNOS-/- mice. Colony size with high EPO treatment also exhibited a marked increase in erythroid cultures from wild type and eNOS-/- mice but not from nNOS-/- mice. Bone marrow transplant from nNOS-/- mice into immunodeficient mice showed engraftment at comparable levels to WT bone marrow transplant. With EPO treatment, the increase in hematocrit was blunted in recipient mice that received with nNOS-/- donor marrow compared with recipient mice that received WT donor marrow. In erythroid cell cultures, addition of nNOS inhibitor resulted in decreased EPO dependent proliferation mediated in part by decreased EPO receptor expression, and decreased proliferation of hemin induced differentiating erythroid cells. Discussion: EPO treatment in mice and in corresponding cultures of bone marrow erythropoiesis suggest an intrinsic defect in erythropoietic response of nNOS-/- mice to high EPO stimulation. Transplantation of bone marrow from donor WT or nNOS-/- mice into recipient WT mice showed that EPO treatment post-transplant recapitulated the response of donor mice. Culture studies suggest nNOS regulation of EPO dependent erythroid cell proliferation, expression of EPO receptor and cell cycle associated genes, and AKT activation. These data provide evidence that nitric oxide modulates EPO dose dependent erythropoietic response.

Regeneration after blood loss and acute inflammation proceeds without contribution of primitive HSCs

AbstractHematopoietic stem cells (HSCs) are the ultimate source of blood and immune cells, and transplantation reveals their unique potential to regenerate all blood lineages lifelong. HSCs are considered a quiescent reserve population under homeostatic conditions, which can be rapidly activated by perturbations to fuel blood regeneration. In accordance with this concept, inflammation and loss of blood cells were reported to stimulate the proliferation of HSCs, which is associated with a decline in their transplantation potential. To investigate the contribution of primitive HSCs to the hematopoietic stress response in the native environment, we use fate mapping and proliferation tracking mouse models. Although primitive HSCs were robustly activated by severe myeloablation, they did not contribute to the regeneration of mature blood cells in response to prototypic hematopoietic emergencies, such as acute inflammation or blood loss. Even chronic inflammatory stimulation, which triggered vigorous HSC proliferation, only resulted in a weak contribution of HSCs to mature blood cell production. Thus, our data demonstrate that primitive HSCs do not participate in the hematopoietic recovery from common perturbations and call for the reevaluation of the concept of HSC-driven stress responses.

ANKRD26 is a new regulator of type I cytokine receptor signaling in normal and pathological hematopoiesis.

Sustained ANKRD26 expression associated with germline ANKRD26 mutations causes thrombocytopenia 2 (THC2), an inherited platelet disorder associated with a predisposition to leukemia. Some patients also present with erythrocytosis and/or leukocytosis. Using multiple human-relevant in vitro models (cell lines, primary patients' cells and patient-derived induced pluripotent stem cells) we demonstrate for the first time that ANKRD26 is expressed during the early steps of erythroid, megakaryocyte and granulocyte differentiation, and is necessary for progenitor cell proliferation. As differentiation progresses, ANKRD26 expression is progressively silenced, to complete the cellular maturation of the three myeloid lineages. In primary cells, abnormal ANKRD26 expression in committed progenitors directly affects the proliferation/differentiation balance for the three cell types. We show that ANKRD26 interacts with and crucially modulates the activity of MPL, EPOR and G-CSFR, three homodimeric type I cytokine receptors that regulate blood cell production. Higher than normal levels of ANKRD26 prevent the receptor internalization that leads to increased signaling and cytokine hypersensitivity. These findings afford evidence how ANKRD26 overexpression or the absence of its silencing during differentiation is responsible for myeloid blood cell abnormalities in patients with THC2.