Nuclear phospholipase C β1 signaling, epigenetics and treatments in MDS

Abstract

Myelodysplastic syndromes (MDS), clonal hematopoietic stem-cell disorders mainly affecting older adult patients, show ineffective hematopoiesis in one or more of the lineages of the bone marrow. Most MDS are characterized by anemia, and a number of cases progresses to acute myeloid leukemia (AML). Indeed, the molecular mechanisms underlying the MDS evolution to AML are still unclear, even though the nuclear signaling elicited by PI-PLCβ1 has been demonstrated to play an important role in the control of the balance between cell cycle progression and apoptosis in MDS cells. Here we review both the role of epigenetic therapy on PI-PLCβ1 promoter and the changes in PI-PLCβ1 expression in MDS patients treated for anemia.

Phosphoinositide-specific phospholipase C in health and disease

“…Given their peculiar roles and their fi ne regulation in physiology, alterations affecting PI-PLC isozymes have been associated with several diseases that can target different tissues and organs (62)(63)(64)(65).…”

Genetic and epigenetic pathways in myelodysplastic syndromes: A brief overview

“…Similarely, in an independent study reported by Follo et al (2009b), the investigators have demonstrated that following treatment with hypomethlating agents, there is a significant reduction of methylation in the nuclear PI-PLCb1 methylation, consequently resulting in increase in gene expression, which is directly correlated with the clinical response in high risk MDS patients. In addition, further studies by Follo et al (2013) demonstrated that specific activation of Akt, mTOR and its down stream effectors occur in high risk MDS patients, which inversely correlates with PI-PLCb1gene expression, Similarley, in the low risk MDS patients EPO, which is normally used to correct anemia Akt activation is associated with PI-PLCb1 down regulation, once again serving as an important biomarker for clinical and hematologic response to EPO therapy. Lastly, the results of studies presented by Boultwood et al (2013) demonstrated that patients with 5q-syndrome and Diamond-Blackfan anemia (DBA), who often suffer from severe macrocytic anemia and exhibit aberrant ribosome biogenesis due to haploinsufficiency of ribosomal protein genes RPS 14 and 19 respestively, show clinical and hematologic response to treatment with the amino acid L-leucine, a translation enhancer.…”

Phosphoinositide-specific Phospholipase C β 1b (PI-PLCβ1b) Interactome: Affinity Purification-Mass Spectrometry Analysis of PI-PLCβ1b with Nuclear Protein

“…We previously reported that in MEL cells, cyclin D3 (3), the transcription factor p45/NF-E2 (enhancer binding protein for the ␤-globin gene) (6), the antigen CD24 (involved in differentiation and hematopoiesis) (7), the splicing factor Sfrs3 (Srp20) (18), and lamin B1 (4) are affected by nuclear PI-PLC␤1, among which Srp20 and lamin B1 were found to be associated with PI-PLC␤1 in co-immunoprecipitation experiments. In recent years, the involvement of PI-PLC␤1 in the development of cancer has been proposed, as studies on myelodysplastic syndrome (MDS) and acute myeloid leukemia have demonstrated that epigenetic and genetic modifications of the PI-PLC␤1 locus occur in patients during MDS progression to acute myeloid leukemia (34). All together, these data make the need to understand the effectors and interactors of PI-PLC␤1 even more urgent, in order to precisely target the mechanisms implicated in these diseases.…”

“…47. As for the current concepts concerning factors promoting hematological malignancies, in which gene mutations, deregulated gene expression, and epigenetic changes are seen as key steps in disease pathogenesis, PI-PLC␤1 was found to be involved in each of these processes (48). The identification of proteins implicated in the epigenetic regulation of gene expression through DNA methylation as PI-PLC␤1 binders was particularly relevant.…”