From clinic to laboratory: Signal transduction analysis and future applications

Abstract Background: Epithelioid hemangioma (EH) of bone is a vascular neoplasm with a ubiquitous distribution, including bone and soft tissue. The clinical behavior of EH is complicated because of its multifocal presentation and rare lymph node involvement. To date, up to 25% EH of bone presents synchronous bone lesions and specific gene alterations. Recently, a novel and recurrent FOS gene rearrangement was present in nearly one third of EH across a variety of locations. Before the discovery of gene rearrangements specific to this rare entity, EH was often misdiagnosed as epithelioid hemangioendothelioma (EHE) or angiosarcoma. Acute Myeloid Leukemia (AML) is characterized by an increase in the number of myeloid cells in the bone marrow and an arrest in their maturation, frequently resulting in impaired hematopoietic differentiation that results in granulocytopenia, thrombocytopenia or anemia, with or without leukocytosis. Currently, Azacitidine is the first-line clinical drug for both MDS and AML, whereas Venetoclax is mainly used for chronic lymphocytic leukemia (CLL) patients with or without 17p deletion. The combination of Venetoclax with Azacitidine is being tested with positive clinical results in AML therapy. However, the molecular mechanisms underlying the effect of this combination therapy are still unclear. Therefore, in this study we analyzed the molecular effects of Azacitidine and Venetoclax combination on the nuclear inositide-dependent pathways, mainly focus on PLC-β1. Aim: This study aimed at describing for the first time a metachronous multifocal lesions case of EH with fatal outcome and analyze the role of inositide pathways in AML.Results: Here we reported the first case of EH with multifocal metachronous bone lesions. This case shows the possible existence of multifocal metachronous EH without producing a fatal outcome. FOS gene rearrangement is critical to assistant the diagnosis of EH. On the other hand, we studied inositide signalling in AML, confirming the IC50 of MOLM-13, HL-60, THP-1 and U-937 hematopoietic cell lines when exposed to Azacitidine and Venetoclax. Moreover, Azacitidine and Venetoclax treatment could induce an increase of the Sub-G0/G1 phase, as well as a G0/G1 arrest in MOLM-13 cells and HL-60 cells. At the same time, it seems to prolong the S phase in U-937 cells. Furthermore, the combination therapy was also able to specifically induce myelopoiesis, as MOLM-13 and THP-1 cells showed an increased expression of CD14. Finally, the combined treatment triggers a higher expression of PLC-β1, which activates the signaling pathway to degrade PKCα