Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas

Fortin, Jérôme; Tian, Ruxiao; Zarrabi, Ida; Hill, Graham; Williams, Eleanor; Sánchez‐Duffhues, Gonzalo; Thorikay, Midory; Ramachandran, Parameswaran; Siddaway, Robert; Wong, Jong Fu; Wu, Annette; Apuzzo, Lorraine N.; Haight, Jillian; You-Ten, Annick; Snow, Bryan E.; Wakeham, Andrew; Goldhamer, David J.; Schramek, Daniel; Bullock, Alex N.; Dijke, Peter ten; Hawkins, Cynthia; Mak, Tak W.

doi:10.1016/j.ccell.2020.02.002

Cited by 66 publications

(56 citation statements)

References 85 publications

(119 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More recent models of DIPG GEMMs have utilized specific genetic alterations such as PDGFB , H3K27M , and p53 [ 79 ] although these models are also not exclusive to the pons . Recently, models of ACVR1 have elucidated that mutant ACVR1 arrests glial cell differentiation and subsequently drives tumorigenesis in pediatric gliomas [ 80 ]. In the future, the development of faithful genetic models of DIPGs that consistently recapitulate both spatiotemporal and molecular tumor characteristics will be vital for identifying novel oncogenic programs and elucidating the temporal and spatial factors which contribute to tumor formation.…”

Section: Experimental Models Of Dipgsmentioning

confidence: 99%

Diffuse intrinsic pontine glioma: current insights and future directions

et al. 2021

View full text Add to dashboard Cite

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor and the leading cause of brain tumor–related death in children. As several clinical trials over the past few decades have led to no significant improvements in outcome, the current standard of care remains fractionated focal radiation. Due to the recent increase in stereotactic biopsies, tumor tissue availabilities have enabled our advancement of the genomic and molecular characterization of this lethal cancer. Several groups have identified key histone gene mutations, genetic drivers, and methylation changes in DIPG, providing us with new insights into DIPG tumorigenesis. Subsequently, there has been increased development of in vitro and in vivo models of DIPG which have the capacity to unveil novel therapies and strategies for drug delivery. This review outlines the clinical characteristics, genetic landscape, models, and current treatments and hopes to shed light on novel therapeutic avenues and challenges that remain.

show abstract

Section: Experimental Models Of Dipgsmentioning

confidence: 99%

Diffuse intrinsic pontine glioma: current insights and future directions

et al. 2021

View full text Add to dashboard Cite

show abstract

“…ALK2 R206H displays mild ligand-independent BMP signalling, as well as increased responsiveness to BMP stimulation. In addition to the c.617G>A ACVR1 mutation (encoding ALK2 R206H ), all mutations detected in FOP and diffuse-intrinsic pontine glioma (DIPG) also show enhanced SMAD1/5/8 responses to BMPs [ 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. Interestingly, the mutant ALK2 does not require its ligand-binding domain to over activate BMP signalling [ 56 ].…”

Section: Aberrant Tgf-β Signalling Underlies Fopmentioning

confidence: 99%

Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva

et al. 2021

Self Cite

View full text Add to dashboard Cite

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites. FOP patients carry heterozygous gene point mutations in activin A receptor type I ACVR1, encoding the bone morphogenetic protein (BMP) type I serine/threonine kinase receptor ALK2, termed activin receptor-like kinase (ALK)2. The mutant ALK2 displays neofunctional responses to activin, a closely related BMP cytokine that normally inhibits regular bone formation. Moreover, the mutant ALK2 becomes hypersensitive to BMPs. Both these activities contribute to enhanced ALK2 signalling and endochondral bone formation in connective tissue. Being a receptor with an extracellular ligand-binding domain and intrinsic intracellular kinase activity, the mutant ALK2 is a druggable target. Although there is no approved cure for FOP yet, a number of clinical trials have been recently initiated, aiming to identify a safe and effective treatment for FOP. Among other targeted approaches, several repurposed drugs have shown promising results. In this review, we describe the molecular mechanisms underlying ALK2 mutation-induced aberrant signalling and ectopic bone formation. In addition, we recapitulate existing in vitro models to screen for novel compounds with a potential application in FOP. We summarize existing therapeutic alternatives and focus on repositioned drugs in FOP, at preclinical and clinical stages.

show abstract

“…Conversely, inhibiting the ACVR1 signaling decreased the cell proliferation in vitro and prolonged mouse survival in vivo. In another study [ 125 ], ACVR1 G328V caused the arrest of the oligodendroglial differentiation and induced gliomas in mice in cooperation with H3b K27M and Pik3ca H1047R [ 125 ]. To date, although the dysregulated ACVR1 signaling may contribute to neurological dysfunction, there is no clinical evidence that patients with FOP have an increased propensity for the development of CNS malignancies including gliomas.…”

Section: Neurologic Dysfunction In Fopmentioning

confidence: 99%

Cardiopulmonary and Neurologic Dysfunctions in Fibrodysplasia Ossificans Progressiva

Khan

Hsiao

2021

Biomedicines

View full text Add to dashboard Cite

Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare but debilitating disorder characterized by spontaneous, progressive, and irreversible heterotopic ossifications (HO) at extraskeletal sites. FOP is caused by gain-of-function mutations in the Activin receptor Ia/Activin-like kinase 2 gene (Acvr1/Alk2), with increased receptor sensitivity to bone morphogenetic proteins (BMPs) and a neoceptor response to Activin A. There is extensive literature on the skeletal phenotypes in FOP, but a much more limited understanding of non-skeletal manifestations of this disease. Emerging evidence reveals important cardiopulmonary and neurologic dysfunctions in FOP including thoracic insufficiency syndrome, pulmonary hypertension, conduction abnormalities, neuropathic pain, and demyelination of the central nervous system (CNS). Here, we review the recent research and discuss unanswered questions regarding the cardiopulmonary and neurologic phenotypes in FOP.

show abstract

Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas

Cited by 66 publications

References 85 publications

Diffuse intrinsic pontine glioma: current insights and future directions

Diffuse intrinsic pontine glioma: current insights and future directions

Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva

Cardiopulmonary and Neurologic Dysfunctions in Fibrodysplasia Ossificans Progressiva

Contact Info

Product

Resources

About