ARID1B, a molecular suppressor of erythropoiesis, is essential for the prevention of Monge’s disease

Azad, Priti; Caldwell, Andrew B.; Ramachandran, Srinivasan; Spann, Nathanael J.; Akbari, Ali; Villafuerte, Francisco C.; Bermudez, Daniela; Zhao, Helen; Poulsen, Orit; Zhou, Dan; Bafna, Vineet; Subramaniam, Shankar; Haddad, Gabriel G.

doi:10.1038/s12276-022-00769-1

Cited by 12 publications

(16 citation statements)

References 52 publications

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“…On the other hand, other subunits are specific to certain processes within one of those lineages. For instance, SMARCE1 is involved in the differentiation of CD4+ and CD8+ T cells [ 64 ], while ARID1B and SMARCD2 regulate erythropoiesis [ 68 ] and granulocytic maturation [ 69 , 70 ], respectively.…”

Section: Swi/snf Complexes and Their Role In Hematopoiesismentioning

confidence: 99%

SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities

et al. 2023

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Hematological malignancies are a highly heterogeneous group of diseases with varied molecular and phenotypical characteristics. SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes play significant roles in the regulation of gene expression, being essential for processes such as cell maintenance and differentiation in hematopoietic stem cells. Furthermore, alterations in SWI/SNF complex subunits, especially in ARID1A/1B/2, SMARCA2/4, and BCL7A, are highly recurrent across a wide variety of lymphoid and myeloid malignancies. Most genetic alterations cause a loss of function of the subunit, suggesting a tumor suppressor role. However, SWI/SNF subunits can also be required for tumor maintenance or even play an oncogenic role in certain disease contexts. The recurrent alterations of SWI/SNF subunits highlight not only the biological relevance of SWI/SNF complexes in hematological malignancies but also their clinical potential. In particular, increasing evidence has shown that mutations in SWI/SNF complex subunits confer resistance to several antineoplastic agents routinely used for the treatment of hematological malignancies. Furthermore, mutations in SWI/SNF subunits often create synthetic lethality relationships with other SWI/SNF or non-SWI/SNF proteins that could be exploited therapeutically. In conclusion, SWI/SNF complexes are recurrently altered in hematological malignancies and some SWI/SNF subunits may be essential for tumor maintenance. These alterations, as well as their synthetic lethal relationships with SWI/SNF and non-SWI/SNF proteins, may be pharmacologically exploited for the treatment of diverse hematological cancers.

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Section: Swi/snf Complexes and Their Role In Hematopoiesismentioning

confidence: 99%

SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities

et al. 2023

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“…We exposed PBMCs-derived native CD34 + cells that were isolated from CMS (n=4) and non-CMS (n=2) subjects to either 5% O2, a hypoxia level that induces significant excessive erythrocytosis in CMS (5), or normoxia (as controls) (Figure 1A). Since we intended to start with a screening experiment, we pooled samples for each group and performed an RNA-seq on the pooled samples to determine the transcriptomic response of the CMS and non-CMS cells to hypoxia.…”

Section: Differences In Long Non-coding Expression Among Cms and Non-...mentioning

confidence: 99%

“…Monge's disease or chronic mountain sickness (CMS) is a clinical syndrome caused by chronic (years) exposure to high altitude hypoxia, such as experienced by people living at Cerro de Pasco in the Andes (1)(2)(3)(4). Excessive Erythrocytosis (EE; Hb ≥21 g/dL in men, Hb ≥19 g/dL in women) is the main feature of CMS, and this excessive pathobiological response to hypoxia has deleterious effects, since a high hematocrit/hemoglobin increases blood viscosity and reduces blood flow to hypoxia-sensitive organs (e.g., brain and heart), often resulting in myocardial infarction, stroke and high mortality in young adults (1,(3)(4)(5)(6)(7). Remarkably, there are individuals who live at the same geographic location and altitude as the CMS subjects but are adapted and do not show any of the traits of the CMS individuals (i.e., adapted or non-CMS).…”

Section: Introductionmentioning

confidence: 99%

Long noncoding RNA HIKER regulates erythropoiesis in Monge’s disease via CSNK2B

Azad¹,

Zhou²,

Tu³

et al. 2023

Journal of Clinical Investigation

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Excessive Erythrocytosis (EE) is a major hallmark of patients suffering from chronic mountain sickness (CMS, Monge's disease) and is responsible for major morbidity and even mortality in early adulthood. We took advantage of unique populations, one living at high altitude (Peru) showing EE, while another population, at the same altitude and region, shows no evidence of EE (non-CMS). Through RNA-seq, we identified and validated the function of a group of long non-coding RNA (lncRNAs) that regulate erythropoiesis in Monge's disease but not in the non-CMS population. Among these lncRNAs is HIKER (Hypoxia Induced Kinasemediated Erythropoietic Regulator)/LINC02228 which we showed plays a critical role in erythropoiesis in CMS cells. Under hypoxia, HIKER modulated CSNK2B (the regulatory subunit of Casein kinase 2). A down-regulation of HIKER down-regulated CSNK2B, remarkably reducing erythropoiesis (<70% reduction of BFUs); furthermore, an up-regulation of CSNK2B on the background of HIKER down-regulation rescued erythropoiesis defects. Pharmacologic inhibition of CSNK2B drastically reduced erythroid colonies (50-75% reduction in BFU colonies) and knock-down of CSNK2B in zebrafish lead to a defect in hemoglobinization (<97% morphants show reduction in hemoglobin levels). We conclude that HIKER regulates erythropoiesis in Monge's disease and acts through at least one specific target, CSNK2B, a casein kinase.

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“…Die Expressionsfähigkeit für ein Suppressor-Gen der Erythropoese, dem sog. ARID1B, scheint für die auffällig unterschiedlichen Suszeptibilitäten für die chronische Höhenkrankheit innerhalb einer konstant in Höhe lebenden Bevölkerung zu sein 5 .…”

Section: Ausgangspunkt Der Hypoxieforschung – Menschliches Leben In G...unclassified

Sauerstoff – immer notwendig, gezielt sparen kann helfen

Stange¹

2022

Zeitschrift für Komplementärmedizin

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SummaryErst seit relativ kurzer Zeit werden biopositive wie -negative Folgen von Hypoxie gleichermaßen konsequent untersucht. Parallel hat sich mit der IHHT bereits eine Therapierichtung etabliert, die technisch zeitgemäß handhabbar ist und bislang keine größeren Sicherheitsprobleme erkennen ließ. Ein therapeutischer Nutzen jenseits der Leistungssteigerung für Gesunde scheint sich vor allem in Fragen der Neuroprotektion und Alternsverzögerung zu manifestieren.

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ARID1B, a molecular suppressor of erythropoiesis, is essential for the prevention of Monge’s disease

Cited by 12 publications

References 52 publications

SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities

SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities

Long noncoding RNA HIKER regulates erythropoiesis in Monge’s disease via CSNK2B

Sauerstoff – immer notwendig, gezielt sparen kann helfen

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