Flt3L is a novel regulator of skeletal myogenesis

Ge, Yejing; Waldemer, Rachel J.; Nalluri, Ramakrishna; Nuzzi, Paul D.; Chen, Jie

doi:10.1242/dev.101865

Cited by 4 publications

(5 citation statements)

References 1 publication

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“…Ingenuity pathway analysis (IPA) showed that the most significantly positive correlation (Z score > 2) after ginsenoside Rd treatment was with the FLT3 signaling pathway (Table 1). It has been reported that FLT3 regulates myogenic differentiation by enhancing the expression of p21 (WAF1/CIP1), a cell cycle inhibitor, resulting in cells exiting the cell cycle (30). We detected increased levels of p21 in D2 myoblasts under FLT3 treatment, and this effect was also seen in ginsenoside Rd-treated D2 myoblasts (Figure 4, A and B).…”

Section: Resultssupporting

confidence: 59%

“…FLT3 is a type III tyrosine kinase, and its mutation in leukemia results in aberrant cell growth (46). To date, there has been only one study to our knowledge reporting FLT3 as necessary for myogenic differentiation; overexpression of FLT3 appeared to promote cell cycle exit and myoblast fusion by inhibiting ERK activity through p120RasGAP (30). In our study, enhanced ERK phosphorylation was observed in D2 myoblasts by recombinant FLT3 (100 ng/mL) treatment as well as ginsenoside Rd (20 μM) treatment (Figure 4, C and D), which is in contrast to the result of Ge et al (30).…”

Section: Discussionmentioning

confidence: 99%

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Duchenne muscular dystrophy hiPSC-derived myoblast drug screen identifies compounds that ameliorate disease in mdx mice

et al. 2020

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Section: Resultssupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Duchenne muscular dystrophy hiPSC-derived myoblast drug screen identifies compounds that ameliorate disease in mdx mice

et al. 2020

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“…PTEN signalling was found to be decreased (z‐score −1.732). While IGF‐1 and IL‐8 have been studied in the context of CC, FLT3 signalling is an emerging new pathway with role in myogenic differentiation . Other significant pathways ( P < 0.05) identified were protein ubiquitination pathway, glucocorticoid signalling, and IL‐4 signalling, findings that are consistent with CC literature on pathway‐based gene expression analysis.…”

Section: Resultssupporting

confidence: 76%

Differentially expressed alternatively spliced genes in skeletal muscle from cancer patients with cachexia

Narasimhan

Greiner

Bathe

et al. 2017

J cachexia sarcopenia muscle

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BackgroundAlternative splicing (AS) is a post‐transcriptional gene regulatory mechanism that contributes to proteome diversity. Aberrant splicing mechanisms contribute to various cancers and muscle‐related conditions such as Duchenne muscular dystrophy. However, dysregulation of AS in cancer cachexia (CC) remains unexplored. Our objectives were (i) to profile alternatively spliced genes (ASGs) on a genome‐wide scale and (ii) to identify differentially expressed alternatively spliced genes (DASGs) associated with CC.MethodsRectus abdominis muscle biopsies obtained from cancer patients were stratified into cachectic cases (n = 21, classified based on International consensus diagnostic framework for CC) and non‐cachectic controls (n = 19, weight stable cancer patients). Human transcriptome array 2.0 was used for profiling ASGs using the total RNA isolated from muscle biopsies. Representative DASG signatures were validated using semi‐quantitative RT–PCR.ResultsWe identified 8960 ASGs, of which 922 DASGs (772 up‐regulated and 150 down‐regulated) were identified at ≥1.4 fold‐change and P < 0.05. Representative DASGs validated by semi‐quantitative RT–PCR confirmed the primary findings from the human transcriptome arrays. Identified DASGs were associated with myogenesis, adipogenesis, protein ubiquitination, and inflammation. Up to 10% of the DASGs exhibited cassette exon (exon included or skipped) as a predominant form of AS event. We also observed other forms of AS events such as intron retention, alternate promoters.ConclusionsOverall, we have, for the first time, conducted global profiling of muscle tissue to identify DASGs associated with CC. The mechanistic roles of the identified DASGs in CC pathophysiology using model systems is warranted, as well as replication of findings in independent cohorts.

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“…One possible mechanism is the inhibition of Fms-like tyrosine kinase 3 (FLT-3) by cabozantinib. FLT-3 is a receptor tyrosine kinase expressed mainly on the membrane of hematopoietic progenitor cells, and a previous study demonstrated that the FLT-3 ligand and FLT-3 signaling pathway are expressed in differentiating myoblasts, and their signaling is a key regulator of skeletal myogenesis [7]. In addition, the FLT-3 inhibitor gilteritinib is known to cause CK elevation [8], which also suggests the possibility of this mechanism.…”

Section: Discussionmentioning

confidence: 99%

Cabozantinib-induced serum creatine kinase elevation and rhabdomyolysis: a retrospective study

Yamanaka

Takemura

Hayashida

et al. 2022

Preprint

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BackgroundRhabdomyolysis is a potentially fatal disease, and elevated serum creatine kinase (CK) is one of the key laboratory findings suggestive of this disease. It is important to distinguish rhabdomyolysis from other diseases because CK elevation can occur in a variety of etiologies. Cabozantinib is one of the standard treatments for patients with renal cell carcinoma, but the frequency of CK elevation with this drug is still unknown.MethodsTo investigate the frequency of serum CK elevation induced by cabozantinib, we retrospectively reviewed the electronic medical records of patients with advanced renal cell carcinoma who received cabozantinib at our institution from April 2020 to March 2021.ResultsSeven patients were included in the study; six experienced serum CK elevation, four were classified as grade 1, and the remaining two as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. In five patients, the time from cabozantinib administration to CK elevation was 14 days. Hypothyroidism can be one of the causes of CK elevation; however, two patients who had hypothyroidism caused by previous treatment were in the euthyroid condition due to hormone replacement. One patient with grade 1 CK elevation developed late-onset immune-related adverse event (irAE) myositis comorbid with suspected myasthenia gravis. One patient with grade 3 CK elevation developed muscle weakness and rhabdomyolysis.ConclusionsCK elevation is a common adverse event induced by cabozantinib. Most patients are asymptomatic and may not be clinically ill. However, physicians should be careful with the rare occurrence of symptomatic serum CK elevation, indicating rhabdomyolysis and neuromuscular irAEs, especially in patients who receive immune checkpoint inhibitors (ICIs).

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Flt3L is a novel regulator of skeletal myogenesis

Cited by 4 publications

References 1 publication

Duchenne muscular dystrophy hiPSC-derived myoblast drug screen identifies compounds that ameliorate disease in mdx mice

Duchenne muscular dystrophy hiPSC-derived myoblast drug screen identifies compounds that ameliorate disease in mdx mice

Differentially expressed alternatively spliced genes in skeletal muscle from cancer patients with cachexia

Cabozantinib-induced serum creatine kinase elevation and rhabdomyolysis: a retrospective study

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