This article is a tad tough to read through because of all the terminologies (jargon) used etc...
However, it is not all that difficult to follow the gist of these findings if one treats it more like an analogy of some mystery and suspense type story.
For example, in Myelofibrosis, Ruxolitinib (Jakafi) is used to suppress the 'Proliferation' of our blood cells, and hopefully thereby create some improvement in Quality of Life (QoL), and maybe even add a few years to our longevity (?) Jakafi therefore works as an Inhibitor (or Blocker) to the Signalling of mutant cells...
Essentially, this article, by a group of Japanese researchers doing the 'Detective' work by planning 'stake-outs' and tracking the movement of their subject groups, (the mutant proteins; inhibitors; chemical compounding treatments; and methods used in those applications), in an endeavour to provide a 'Cause & Effect' at the sub-atomic cellular levels. The Golgi apparatus, which is a transactional part, (organelle), of a cells anatomy:
"The Golgi apparatus, also called Golgi complex or Golgi body, is a membrane-bound organelle found in eukaryotic cells (cells with clearly defined nuclei) that is made up of a series of flattened stacked pouches called cisternae. It is located in the cytoplasm next to the endoplasmic reticulum and near the cell nucleus."
And it doesn't really matter that most of us don't know much about the Golgi at this stage, just that they are a part of a Leukaemic cell's structure. What is important is that we understand it is where much of the cells directions "Oncologic Signals" are coming from, (from those aberrant cellular mutations), and that these new chemical compounds, (M-COPA), might be helping to stem proliferation by 'Blocking' their signals to produce more of those aberrant cancer cells etc.
Abstract
Background
KIT is a member of the type III receptor tyrosine kinase (RTK) family that includes platelet-derived growth factor receptor A/B (PDGFRA/B), fms, and fms-like tyrosine kinase 3 (FLT3) [1,2,3]. It is known to participate in tyrosine phosphorylation signals at the PM, ensuring cell growth and survival in hematopoietic cells, mast cells, interstitial cells of Cajal, germ cells, and melanocytes [4,5,6].
KIT is composed of N-glycosylated immunoglobulin domains in the amino-terminal extracellular portion, transmembrane region, juxta-membrane (JM) region, and the carboxy-terminal cytoplasmic tyrosine kinase domain [6, 7]. Stem cell factor (SCF), a ligand for KIT, stimulates KIT phosphorylation on selective tyrosine residues, such as Y703 and Y721, and these phospho-tyrosines serve as docking sites for downstream molecules [7,8,9]. SCF-KIT activates the phosphatidyl 3-kinase-AKT pathway and the RAS-MEK-ERK cascade, which control gene expression, metabolism, and cytoskeletal architecture [6, 9,10,11]. The JM region plays a role in autoinhibition of the receptor through intra-molecular binding [12]. Thus, constitutively active mutations of KIT allow host cells to autonomously proliferate, resulting in the development of AML, MCL, GIST, germ cell tumors, and melanoma [6, 13,14,15,16]. In particular, KIT mutations in the JM region (eg, V560G, deletion etc.) are found in 70% of GIST patients [17,18,19]. A tyrosine kinase inhibitor, imatinib mesylate (Gleevec), has been developed for the treatment of GIST, and it has dramatically improved the prognosis of patients [19, 20]. However, KIT-bearing mutations in the kinase activation loop (AL), such as D816V, cause a loss of sensitivity to imatinib [17, 18, 21, 22]. In comparison to JM mutants (mut), KITN822K is also imatinib-resistant but to a lesser degree than KITD816V [17, 22, 23].
Previously, we reported that in MCL, KITD816V (human) and KITD814Y (mouse) activate AKT and the signal transducer and activator of transcription 5 (STAT5) in EL and on the ER, respectively (Table 1) [24, 25]. Furthermore, previous studies showed that in cells other than those of MCL, such as GIST and NIH3T3 cells, JM-mut or AL-mut accumulates on the Golgi apparatus, where it initiates oncogenic signals (Table 1) [26,27,28,29]. These studies raised important questions as to whether mutant KIT initiates signaling from intracellular compartments in other cancers such as AML, and whether the mutation status of KIT affects the platform for oncogenic signaling.
Conclusions
In conclusion, we show that in leukemia cells, N822K- and V560G-mutated KIT can initiate growth signals in lipid rafts of the Golgi apparatus. These observations provide new insights into the pathogenic role of KIT mutants as well as into that of other mutant signaling molecules. Moreover, from a clinical point of view, our findings offer a new strategy for leukemia treatment through that blocks the incorporation of KIT mutants into the lipid rafts of the Golgi.
According to Prof. Shiina and the group, this study reveals that the novel compound M-COPA can be used to block transport of KIT from the ER to the Golgi (where it is activated and carries out downstream oncogenic signaling). The scientists say that the compound M-COPA has applications such as treatment of patients with AML, improved prognosis for these patients, and improvement in the quality of life of these patients. Prof. Shiina concludes by stating, "Currently, the synthesis of various M-COPA analogs is progressing every day at our university, and their inhibitory effects against hematological cancers and solid cancers (stomach cancer, lung cancer, ovarian cancer, etc.) are being verified."
REFERENCE
Yuuki Obata et al. 2019. "N822K- or V560G-mutated KIT activation preferentially occurs in lipid rafts of the Golgi apparatus in leukemia cells". Cell Communication and Signaling (2019). DOI: 10.1186/s12964-019-0426-3
https://biosignaling.biomedcentral.com/ ... 019-0426-3 (Link to Full Text)