Inositide-dependent signaling pathways as new therapeutic targets in myelodysplastic syndromes

ABSTRACT

Introduction: Nuclear inositide signaling pathways specifically regulate cell proliferation and differentiation. Interestingly, the modulation of nuclear inositides in hematological malignancies can differentially affect erythropoiesis or myelopoiesis. This is particularly important in patients with myelodysplastic syndromes (MDS), who show both defective erythroid and myeloid differentiation, as well as an increased risk of evolution into acute myeloid leukemia (AML).

Areas covered: This review focuses on the structure and function of specific nuclear inositide enzymes, whose impairment could be linked with disease pathogenesis and cancer. The authors, stemming from literature and published data, discuss and describe the role of nuclear inositides, focusing on specific enzymes and demonstrating that targeting these molecules could be important to develop innovative therapeutic approaches, with particular reference to MDS treatment.

Expert opinion: Demethylating therapy, alone or in combination with other drugs, is the most common and current therapy for MDS patients. Nuclear inositide signaling molecules have been demonstrated to be important in hematopoietic differentiation and are promising new targets for developing a personalized MDS therapy. Indeed, these enzymes can be ideal targets for drug design and their modulation can have several important downstream effects to regulate MDS pathogenesis and prevent MDS progression to AML.

KEYWORDS:

• Myelodysplastic syndromes
• nuclear inositides
• PI-PLCbeta1
• PI-PLCgamma1
• PI3K/Akt/mTOR

Article highlights

• Nuclear inositides, such as phosphoinositide-specific phospholipase C (PI-PLC) beta1 and PI-PLCgamma1, represent an independent circuit of regulation for cell metabolism, but particularly for nuclear-specific functions, that can be affected in cancer cells.

• Nuclear PI-PLCbeta1 and PI-PLCgamma1 are implicated in normal and pathological hematopoiesis, showing a different behavior on the myeloid and erythroid compartments, thus inducing distinct signaling pathways according to the differentiation lineage.

• In MDS patients, nuclear PI-PLCbeta1 increase is specifically associated with myeloid differentiation and a longer response to demethylating drugs, while PI-PLCgamma1 level is related to the degree of erythroid activation.

• Nuclear PI-PLCbeta1 and PI-PLCgamma1 signal transduction pathways are interconnected with the activation of the PI3K/Akt/mTOR axis, which is specifically associated with leukemogenesis and can therefore be activated during MDS progression to AML.

• Targeting nuclear PI-PLCbeta1 and PI-PLCgamma1 could be important for a better regulation of MDS cell proliferation and differentiation, and could also be an alternative treatment to overcome resistance to PI3K/Akt inhibitors in MDS patients.

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Declaration of interest

The authors were supported by the Italian Ministry of University Research (MIUR) Fund for Investment in Basic Research (FIRB). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.