30 research outputs found
Clonal Activation of Akt in Low-Risk MDS Patients with Del(5q) treated with Lenalidomide
The activation of inositide signalling pathways, such as Akt/mTOR, has been demonstrated in high-risk MDS (1). Lenalidomide is currently used in the treatment of del(5q) low-risk MDS patients, where it may suppress the del(5q) clone and restore a normal erythropoiesis, via inhibition of Akt phosphorylation (2). Here, we studied the expression of inositide signalling molecules in 6 low-risk MDS patients who were given Lenalidomide by immunocytochemistry and Real-Time PCR. In our case series, 4 out of 6 del(5q) low-risk MDS patients responded to Lenalidomide and showed an activation of erythropoiesis, in that Beta-Globin levels increased, as compared with baseline. Moreover, these subjects also displayed an activation of PI-PLCgamma1 and Akt. Interestingly, Akt resulted to be specifically phosphorylated in cells not showing the 5q deletion, hinting at a clonal activation of this pathway. The 2 non responder patients early discontinued Lenalidomide for adverse events, and for these patients neither a clinical assessment of Lenalidomide effect, nor a molecular analysis, were possible. Our data show Akt/PI-PLCgamma1 activation during Lenalidomide treatment, and confirm the activation of erythropoiesis in responder patients. In addition, our results indicate that Akt is specifically phosphorylated in the 5q+ clone. Therefore, it is conceivable that Lenalidomide strengthens the proliferation of the 5q+ clone, whilst the del(5q) clone undergoes an apoptotic process, allowing the restoration of the normal erythropoiesis. This is extremely important, not only for MDS pathogenesis, but also for the development of innovative targeted therapies
Glycogen Synthase Kinase-3 and phospholipase C-beta signalling: Roles and possible interactions in myelodysplastic syndromes and acute myeloid leukemia
GSK-3 and PLCbeta enzymes are responsible for the regulation of several signalling pathways related to many cellular functions. In hematopoietic cells, GSK-3 deficiency is correlated with an MDS-like phenotype and with leukemogenesis, showing a prognostic potential in AML cells. GSK-3 interacts with Wnt or MAPK signalling, but it is also linked to PI3K/Akt/mTOR pathways to regulate cell proliferation and apoptosis of hematopoietic stem cell progenitors. PLCbeta enzymes are involved in cell cycle progression of hematopoietic, MDS/AML and immune cells, through activation of PKC or calcium signalling. Of note, a PLCbeta1/PKCalpha pathway is modulated during MDS pathogenesis, with a specific involvement of the inositides localized in the nucleus. Here we focus on GSK-3 and PLCbeta signalling, describing the many evidences that underline the pivotal role of both GSK-3 and PLCbeta-dependent pathways in MDS/AML, their association with therapy and their possible interactions
Nuclear phospholipase C signaling through type 1 IGF receptor and its involvement in cell growth and differentiation
The existence of a nuclear polyphosphoinositol metabolism, independent from that at the plasma cell membrane, is now widely recognized. Specific changes in the nuclear phosphatidylinositol (PtdIns) metabolism have been implicated in cell growth, differentiation and neoplastic transformation. Here, the main features of nuclear inositol lipid signaling through type I IGF receptor, is reviewed with particular attention to the role of inositide-specific phospholipase C (PI-PLC) beta 1 in cell proliferation and differentiation, due to the peculiar localization of this molecule in the nuclear compartment
B-all complexity: Is targeted therapy still a valuable approach for pediatric patients?
B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy that arises from the clonal expansion of transformed B-cell precursors and predominately affects childhood. Even though significant progresses have been made in the treatment of B-ALL, pediatric patients\u2019 outcome has to be furtherly increased and alternative targeted treatment strategies are required for younger patients. Over the last decade, novel approaches have been used to understand the genomic landscape and the complexity of the molecular biology of pediatric B-ALL, mainly next generation sequencing, offering important insights into new B-ALL subtypes, altered pathways, and therapeutic targets that may lead to improved risk stratification and treatments. Here, we will highlight the up-to-date knowledge of the novel B-ALL subtypes in childhood, with particular emphasis on altered signaling pathways. In addition, we will discuss the targeted therapies that showed promising results for the treatment of the different B-ALL subtypes
PI-PLCβ1 gene copy number alterations in breast cancer
Deregulation of signal transduction pathways frequently confers selective biological advantages to tumors. Phosphoinositides play an essential role in numerous cellular functions and, among the enzymes implicated in these processes, phosphoinositide-specific phospholipase C β1 (PI-PLCβ1) is one of the key regulators. In the present study, a fluorescence in situ hybridization (FISH) approach was used to investigate PI-PLCβ1 gene copy number alterations in various types of breast cancer differing in their invasiveness and proliferative activity, according to their mitotic index. At the molecular level, we also performed both real-time PCR and immunohistochemical analyses on PI-PLCβ1 to further investigate its expression in primary breast cancers. Finally, we analyzed the correlation between PI-PLCβ1 gene copy number and clinicopathological parameters. Our results show that most of our cases had aneusomies on the PI-PLCβ1 locus (20p12) and amplification of this specific region was the most frequent alteration observed. Our findings also indicate that the amplification of the region containing the PI-PLCβ1 gene was mostly related to the mitotic index, rather than to the invasion status. Finally, even though our case series is limited, PI-PLCβ1 gene amplification seems to be correlated to clinicopathological parameters
Prolonged hypoxia delays aging and preserves functionality of human amniotic fluid stem cells
Human amniotic fluid stem cells (hAFSCs) are an emerging tool in regenerative medicine because they have the ability to differentiate into various lineages and efficiently improve tissue regeneration with no risk of tumorigenesis. Although hAFSCs are easily isolated from the amniotic fluid, their expansion ex vivo is limited by a quick exhaustion which impairs replicative potential and differentiation capacity. In this study, we evaluate various aging features of hAFSCs cultured at different oxygen concentrations. We show that low oxygen (1% O2) extends stemness and proliferative features, and delays induction of senescence-associated markers. Hypoxic hAFSCs activate a metabolic shift and increase resistance to pro-apoptotic stimuli. Moreover, we observe that cells at low oxygen remain capable of osteogenesis for prolonged periods of time, suggesting a more youthful phenotype. Together, these data demonstrate that low oxygen concentrations might improve the generation of functional hAFSCs for therapeutic use by delaying the onset of cellular aging
Nuclear PI-PLC \u3b21 and Myelodysplastic Syndromes: From Bench to Clinics
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. A number of
MDS progresses to acute myeloid leukemia (AML) with the involvement of genetic and epigenetic
mechanisms affecting PI-PLC \u3b21. The molecular mechanisms underlying the MDS evolution to AML are
still unclear, even though it is now clear that the nuclear signaling elicited by PI-PLC \u3b21, Cyclin D3, and Akt
plays an important role in the control of the balance between cell cycle progression and apoptosis in both
normal and pathologic conditions. Moreover, a correlation between other PI-PLCs, such as PI-PLC \u3b23, kinases
and phosphatases has been postulated in MDS pathogenesis. Here, we review the findings hinting at the role
of nuclear lipid signaling pathways in MDS, which could become promising therapeutic targets
Nuclear phosphoinositide specific phospholipase C (PI-PLC)-ß1: a central intermediary in nuclear lipid-dependent signal transduction
Several studies have demonstrated the
existence of an autonomous intranuclear phosphoinositide
cycle that involves the activation of nuclear PIPLC
and the generation of diacylglycerol (DG) within
the nucleus. Although several distinct isozymes of PIPLC
have been detected in the nucleus, the isoform that
has been most consistently highlighted as being nuclear
is PI-PLC-ß1. Nuclear PI-PLC-ß1 has been linked with
either cell proliferation or differentiation. Remarkably,
the activation mechanism of nuclear PI-PLC-ß1 has been
shown to be different from its plasma membrane
counterpart, being dependent on phosphorylation
effected by p44/42 mitogen activated protein (MAP)
kinase. In this review, we report the most up-dated
findings about nuclear PI-PLC-ß1, such as the
localization in nuclear speckles, the activity changes
during the cell cycle phases, and the possible
involvement in the progression of myelodisplastic
syndrome to acute myeloid leukemia