Two Receptors, Two Isoforms, Two Cancers: Comprehensive Analysis of KIT and TrkA Expression in Neuroblastoma and Acute Myeloid Leukemia

Abstract

Pediatric cancers represent a wide variety of different tumors, though they have unique features that distinguish them from adult cancers. Receptor tyrosine kinases KIT and TrkA functions in AML and NB, respectively, are well-characterized. Though expression of these receptors is found in both tumors, little is known about KIT function in NB and TrkA in AML. By combining gene enrichment analysis with multidimensional scaling we showed that pediatric AMLs with t(8;21) or inv16 and high KIT expression levels stand out from other AML subtypes as they share prominent transcriptomic features exclusively with KIT-overexpressing NBs. We showed that AML cell lines had a predominant expression of an alternative TrkAIII isoform, which reportedly has oncogenic features, while NB cell lines had dominating TrkAI-II isoforms. NB cells, on the other hand, had an abnormal ratio of KIT isoforms as opposed to AML cells. Both SCF and NGF exerted protective action against doxorubicin and cytarabine for t(8;21) AML and NB cells. We identified several gene sets both unique and common for pediatric AML and NB, and this expression is associated with KIT or TrkA levels. NMU, DUSP4, RET, SUSD5, NOS1, and GABRA5 genes are differentially expressed in NBs with high KIT expression and are associated with poor survival in NB. We identified HOXA10, BAG3, and MARCKS genes that are connected with TrkA expression and are marker genes of poor outcome in AML. We also report that SLC18A2, PLXNC1, and MRPL33 gene expression is associated with TrkA or KIT expression levels in both AML and NB, and these genes have a prognostic value for both cancers. Thus, we have provided a comprehensive characterization of TrkA and KIT expression along with the oncogenic signatures of these genes across two pediatric tumors.

Abnormal Expression of Mitochondrial Ribosomal Proteins and Their Encoding Genes with Cell Apoptosis and Diseases

“…In cancers of the blood system, MRPL33 affects the receptor tyrosine kinase TrkA or KIT expression levels in acute myeloid leukemia (AML) and neuroblastoma, which has a prognostic value for both types of cancer [ 31 ]. In the study of the first recurrence of AML patients, AML cells were significantly characterized by increased levels of mitochondrial functional important proteins such as MRPL21 and MRPS37, which may guide treatment strategies to reduce the chemotherapeutic resistance to recurrent AML [ 23 ].…”

Pathophysiological roles of myristoylated alanine-rich C-kinase substrate (MARCKS) in hematological malignancies

“…In addition to its role in the development and progression of hematological malignancies, MARCKS has been implicated in defining the overall outcome in several blood cancers. A high expression of MARCKS has been reported to be associated with an overall poor disease prognosis in AML [ 116 ]. Research from our lab investigating the role of MARCKS in hematological malignancies provided the earliest evidence of its involvement in drug-resistant multiple myeloma (MM), chiefly against the proteasomal inhibitor bortezomib [ 157 ].…”

Comprehensive single-cell gene and isoform expression analysis reveals signatures of ageing in haematopoietic stem and progenitor cells

“…These isoforms encode proteins differing in length by 4 amino acids (KGNN) which, when absent, results in the loss of a low-complexity region in the juxtamembrane extracellular region of the protein. The human equivalent of these variants have been shown to display distinct signalling activities [20][21][22] .…”

“…To highlight the impact of additional long-read sequencing in scRNA-seq studies, we screened the dataset to identify AS events in key transcription factors (TFs) from a regulatory network derived from single-cell studies of haematopoiesis 17 These isoforms encode proteins differing in length by 4 amino acids (KGNN) which, when absent, results in the loss of a low-complexity region in the juxtamembrane extracellular region of the protein. The human equivalent of these variants have been shown to display distinct signalling activities [20][21][22] .…”