Inhibition of Tropomyosin Receptor Kinase A Signaling Negatively Regulates Megakaryopoiesis and induces Thrombopoiesis

Abstract

Neurotrophin signaling modulates the differentiation and function of mature blood cells. The expression of neurotrophin receptors and ligands by hematopoietic and stromal cells of the bone marrow indicates that neurotrophins have the potential to regulate hematopoietic cell fate decisions. This study investigates the role of neurotrophins and Tropomyosin receptor kinases (Trk) in the development of megakaryocytes (MKs) and their progeny cells, platelets. Results indicate that primary human MKs and MK cells lines, DAMI, Meg-01 and MO7e express TrkA, the primary receptor for Nerve Growth Factor (NGF) signaling. Activation of TrkA by NGF enhances the expansion of human MK progenitors (MKPs) and, to some extent, MKs. Whereas, inhibition of TrkA receptor by K252a leads to a 50% reduction in the number of both MKPs and MKs and is associated with a 3-fold increase in the production of platelets. In order to further confirm the role of TrkA signaling in platelet production, TrkA deficient DAMI cells were generated using CRISPR-Cas9 technology. Comparative analysis of wild-type and TrkA-deficient Dami cells revealed that loss of TrkA signaling induced apoptosis of MKs and increased platelet production. Overall, these findings support a novel role for TrkA signaling in platelet production and highlight its potential as therapeutic target for Thrombocytopenia.

Characterization of Long Non-coding RNA Profile in RD and SH-SY5Y Cells Infected by CV-B5 using RNA Sequencing

“…Previous studies have reported that the neurotrophin signaling pathway can regulate growth, differentiation, and apoptosis of neurons through p75 neurotrophin receptor and tyrosine kinase receptor [35; 36]. ErbB signaling pathway modulates neural development, cell proliferation, and differentitation and is also associated with neurodevelopment disorders [37]. The above-mentioned results suggest that the CV-B5 can lead to neurogenic diseases.…”

Searching match for single-cell open-chromatin profiles in large pools of single-cell transcriptomes and epigenomes for reference supported analysis

“…Clustering of K562 scATAC-seq profiles using their low dimension projections in terms of match scores with reference cells revealed two major clusters (Figure 2c-d). For K562 cells belonging to the smaller cluster, some of the most frequently enriched genes, such as NTRK3 (TRKC) 14 and MAF have higher expression in megakaryocytes than erythrocytes (see cluster-1 in Figure 2c-d). MAF is known to cause differentiation of hematopoietic progenitor cells towards megakaryocytes and reduction of its transformation towards erythroid lineage 15 .…”

Discovery of a benzimidazole-based dual FLT3/TrKA inhibitor targeting acute myeloid leukemia

“…Several studies have investigated the role of tropomyosin receptor kinase A (TrKA) in AML [43][44][45][46] . TrKA is a receptor tyrosine kinase normally responsible for the survival and differentiation of neuronal tissue 47 and is additionally implicated in early hematopoiesis 48,49 . TrKA gene fusions and overexpression may contribute to AML growth and survival 45 and although the presence of TrKA fusions sensitized hematopoietic malignancies to TrKA inhibitors 46 , the use of these kinase inhibitors as a single agent is not lethal in AML.…”