Key signaling pathways within the bone marrow microenvironment (BMM), such as Notch, Phosphoinositide-Specific Phospholipase C (PI-PLCs), Transforming Growth Factor β (TGF-β), and Nuclear Factor Kappa B (NF-κB), play a vital role in the progression of myelodysplastic neoplasms (MDS). Among the various BMM cell types, mesenchymal stromal cells (MSCs) are particularly central to these pathways. While these signaling routes can independently affect both MSCs and hematopoietic stem cells (HSCs), they most importantly alter the dynamics of their interactions, leading to abnormal changes in survival, differentiation, and quiescence. Notch and PI-PLC signaling facilitate intercellular communication, TGF-β promotes quiescence and suppresses hematopoiesis, and NF-κB-driven inflammatory responses foster an environment detrimental to normal hematopoiesis. This review highlights the role of these pathways within the MDS microenvironment, driving the development and progression of the disease and paving the way for new possible therapeutic strategies.

The liquid-liquid phase separation in the cell nucleus regulates various processes such as gene regulation and transcription control, chromatin organization, and DNA repair. A plethora of proteins and RNAs contribute to the formation of biomolecular condensates and recently, several nuclear phosphoinositides were shown to be a part of these membrane-less complexes within the nucleus as well. Here we lipid-interacting RNA sequencing (LIPRNAseq) and confocal microscopy to uncover the RNA-binding capacity and localization of phosphatidylinositol 4,5 bisphosphate (PIP2). We discovered the consensus PIP2-binding AU-rich RNA motif and identified long non-coding RNA HANR (lncHANR) to colocalize with PIP2 in the proximity to the nucleolus in the perinucleolar compartment (PNC). Colocalization studies with different nuclear markers reveal that PIP2-HANR presence in the PNC correlates with oncogenic super-enhancers, and both PNC and oncogenic enhancers are part of the same structure. As lncHANR, PNC, and oncogenic super-enhancers are associated with cancer cell lines and tumors, we suggest that they can serve as interchangeable prognostic markers. Understanding of the interplay between lipid metabolism, and lncRNAs in subnuclear compartment phase separation can lead to future improvement in treatment strategies and personalized cancer management approaches.

The phosphoinositide 3-kinase (PI3K) superfamily includes lipid kinases (PI3Ks and type III PI4Ks) and a group of PI3K-like Ser/Thr protein kinases (PIKKs: mTOR, ATM, ATR, DNA-PKcs, SMG1 and TRRAP) that have a conserved C-terminal kinase domain. A common feature of the superfamily is that they have very low basal activity that can be greatly increased by a range of regulatory factors. Activators reconfigure the active site, causing a subtle realignment of the N-lobe of the kinase domain relative to the C-lobe. This realignment brings the ATP-binding loop in the N-lobe closer to the catalytic residues in the C-lobe. In addition, a conserved C-lobe feature known as the PIKK regulatory domain (PRD) also can change conformation, and PI3K activators can alter an analogous PRD-like region. Recent structures have shown that diverse activating influences can trigger these conformational changes, and a helical region clamping onto the kinase domain transmits regulatory interactions to bring about the active site realignment for more efficient catalysis. A recent report of a small-molecule activator of PI3Kα for application in nerve regeneration suggests that flexibility of these regulatory elements might be exploited to develop specific activators of all PI3K superfamily members. These activators could have roles in wound healing, anti-stroke therapy and treating neurodegeneration. We review common structural features of the PI3K superfamily that may make them amenable to activation.

The intricate interplay between lamins and chromatin underpins the structural integrity and functional organization of the eukaryotic nucleus. Lamins, type V intermediate filament proteins, form a robust meshwork beneath the inner nuclear membrane that is crucial for sustaining nuclear architecture through interactions with lamin-associated domains (LADs). LADs are predominantly heterochromatic regions in which compacted chromatin is enriched at the nuclear periphery, interacting with lamins and lamin-associated proteins. Disruptions of these interactions are implicated in a spectrum of diseases, including laminopathies, cancer, and age-related pathologies, highlighting the importance of lamin-LAD interactions. Thus, a detailed understanding of lamin-chromatin interactions may provide new insights into chromatin organization and shed light on the mechanism behind certain disease states. Here, we discuss the current state of knowledge of lamin-chromatin interactions from a biochemical and structural point of view.

Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a genetic disease associated with renal, endocrine, neurological, skin and immune defects. SPLIS is caused by inactivating mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). SPL catalyzes the irreversible degradation of the bioactive sphingolipid sphingosine-1-phosphate (S1P), a key regulator of lymphocyte egress. The SPL reaction represents the only exit point of sphingolipid metabolism, and SPL insufficiency causes widespread sphingolipid derangements that could additionally contribute to immunodeficiency. Herein, we review SPLIS, the sphingolipid metabolic pathway, and various roles sphingolipids play in immunity. We then explore SPLIS-related immunodeficiency by analyzing data available in the published literature supplemented by medical record reviews in ten SPLIS children. We found 93% of evaluable SPLIS patients had documented evidence of immunodeficiency. Many of the remainder of cases were unevaluable due to lack of available immunological data. Most commonly, SPLIS patients exhibited lymphopenia and T cell-specific lymphopenia, consistent with the established role of the S1P/S1P1/SPL axis in lymphocyte egress. However, low B and NK cell counts, hypogammaglobulinemia, and opportunistic infections with bacterial, viral and fungal pathogens were observed. Diminished responses to childhood vaccinations were less frequently observed. Screening blood tests quantifying recent thymic emigrants identified some lymphopenic SPLIS patients in the newborn period. Lymphopenia has been reported to improve after cofactor supplementation in some SPLIS patients, indicating upregulation of SPL activity. A variety of treatments including immunoglobulin replacement, prophylactic antimicrobials and special preparation of blood products prior to transfusion have been employed in SPLIS. The diverse immune consequences in SPLIS patients suggest that aberrant S1P signaling may not fully explain the extent of immunodeficiency. Further study will be required to fully elucidate the complex mechanisms underlying SPLIS immunodeficiency and determine the most effective prophylaxis against infection.

Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). Mammalian DGK comprise ten isozymes (α–κ) that regulate a wide variety of physiological and pathological events. Recently, we revealed that DGK isozymes use saturated fatty acid (SFA)/monosaturated fatty acid (MUFA)-containing and docosahexaenoic acid (22:6)-containing DG species, but not phosphatidylinositol (PI) turnover-derived 18:0/20:4-DG. For example, DGKδ, which is involved in the pathogenesis of type 2 diabetes, preferentially uses SFA/MUFA-containing DG species, such as 16:0/16:0- and 16:0/18:1-DG species, in high glucose-stimulated skeletal muscle cells. Moreover, DGKδ, which destabilizes the serotonin transporter (SERT) and regulates the serotonergic system in the brain, primarily generates 18:0/22:6-PA. Furthermore, 16:0/16:0-PA is produced by DGKζ in Neuro-2a cells during neuronal differentiation. We searched for SFA/MUFA-PA- and 18:0/22:6-PA-selective binding proteins (candidate downstream targets of DGKδ) and found that SFA/MUFA-PA binds to and activates the creatine kinase muscle type, an energy-metabolizing enzyme, and that 18:0/22:6-PA interacts with and activates Praja-1, an E3 ubiquitin ligase acting on SERT, and synaptojanin-1, a key player in the synaptic vesicle cycle. Next, we searched for SFA/MUFA-DG-generating enzymes upstream of DGKδ. We found that sphingomyelin synthase (SMS)1, SMS2, and SMS-related protein (SMSr) commonly act as phosphatidylcholine (PC)-phospholipase C (PLC) and phosphatidylethanolamine (PE)-PLC, generating SFA/MUFA-DG species, in addition to SMS and ceramide phosphoethanolamine synthase. Moreover, the orphan phosphatase PHOSPHO1 showed PC- and PE-PLC activities that produced SFA/MUFA-DG. Although PC- and PE-PLC activities were first described 70–35 years ago, their proteins and genes were not identified for a long time. We found that DGKδ interacts with SMSr and PHOSPHO1, and that DGKζ binds to SMS1 and SMSr. Taken together, these results strongly suggest that there are previously unrecognized signal transduction pathways that include DGK isozymes and generate and utilize SFA/MUFA-DG/PA or 18:0/22:6-DG/PA but not PI-turnover-derived 18:0/20:4-DG/PA.

Fructose 1,6-bisphosphatase (FBP) is a regulatory enzyme of gluconeogenesis that also influences in a non-catalytic manner – via protein-protein interactions – cell cycle-dependent events, mitochondria biogenesis and polarization, synaptic plasticity and even cancer progression. FBP reduces glycolytic capacity of cells via blocking HIF-1α transcriptional activity and modulating NF-κB action, and influences oxidative metabolism by binding to c-MYC. Because FBP limits the energy-producing potential of cells and because a reduction of FBP amounts is observed in cancer cells, FBP is considered to be an anti-oncogenic protein. This is supported by the observation that cancer cells overexpress aldolase A (ALDOA), a pro-oncogenic protein that can bind to FBP and potentially block its anti-oncogenic activity. Interestingly, only the muscle isozyme of FBP (FBP2) interacts strongly with ALDOA, whereas the binding of the liver isozyme (FBP1) to ALDOA is more than an order of magnitude weaker.Here, we briefly review the most important evidence supporting the anti-oncogenic function of FBP and discuss what structural properties of the two FBP isozymes allow FBP2, rather than FBP1, to exert more flexible anticancer functions.