Enhanced IL-36R signaling promotes barrier impairment and inflammation in skin and intestine

Deficiency in interleukin-36R (IL-36R) antagonist caused by loss-of-function mutations in IL-36RN leads to DITRA (deficiency of IL-36 receptor antagonist), a rare inflammatory human disease that belongs to a subgroup of generalized pustular psoriasis (GPP). We report a functional genetic mouse model of DITRA with enhanced IL-36R signaling analogous to that observed in patients with DITRA, which provides new insight into our understanding of the IL-36 family of molecules in regulating barrier integrity across multiple tissues. Humanized DITRA-like mice displayed increased skin inflammation in a preclinical model of psoriasis, and in vivo blockade of IL-36R pathway using anti-human IL-36R antibody ameliorated imiquimod-induced skin pathology as both prophylactic and therapeutic treatments. Deeper characterization of the humanized DITRA-like mice revealed that deregulated IL-36R signaling promoted tissue pathology during intestinal injury and led to impairment in mucosal restoration in the repair phase of chronic dextran sulfate sodium (DSS)–induced colitis. Blockade of IL-36R pathway significantly ameliorated DSS-induced intestinal inflammation and rescued the inability of DITRA-like mice to recover from mucosal damage in vivo. Our results indicate a central role for IL-36 in regulating proinflammatory responses in the skin and epithelial barrier function in the intestine, suggesting a new therapeutic potential for targeting the IL-36R axis in psoriasis and at the later stages of intestinal pathology in inflammatory bowel disease.

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Long-lasting analgesia via targeted in situ repression of NaV1.7 in mice

Science Translational Medicine ◽

10.1126/scitranslmed.aay9056 ◽

2021 ◽

Vol 13 (584) ◽

pp. eaay9056 ◽

Cited By ~ 1

Author(s):

Ana M. Moreno ◽

Fernando Alemán ◽

Glaucilene F. Catroli ◽

Matthew Hunt ◽

Michael Hu ◽

...

Keyword(s):

Chronic Pain ◽

Therapeutic Potential ◽

Thermal Hyperalgesia ◽

Structural Similarity ◽

Loss Of Function ◽

Sensory Afferents ◽

Inflammatory State ◽

Epigenetic Repression

Current treatments for chronic pain rely largely on opioids despite their substantial side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in NaV1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between NaV subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of NaV1.7 in primary afferents via epigenome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)–dCas9 and zinc finger proteins at the spinal level as a potential treatment for chronic pain. Toward this end, we first optimized the efficiency of NaV1.7 repression in vitro in Neuro2A cells and then, by the lumbar intrathecal route, delivered both epigenome engineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain, and BzATP-induced pain. Our results show effective repression of NaV1.7 in lumbar dorsal root ganglia, reduced thermal hyperalgesia in the inflammatory state, decreased tactile allodynia in the neuropathic state, and no changes in normal motor function in mice. We anticipate that this long-lasting analgesia via targeted in vivo epigenetic repression of NaV1.7 methodology we dub pain LATER, might have therapeutic potential in management of persistent pain states.

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Biological and Therapeutic Potential of Mir-155, 585 and Let-7f in Myeloma in Vitro and In Vivo.

Blood ◽

10.1182/blood.v114.22.833.833 ◽

2009 ◽

Vol 114 (22) ◽

pp. 833-833

Author(s):

Sophia Adamia ◽

Mariateresa Fulciniti ◽

Herve Avet-Loiseau ◽

Samir B Amin ◽

Parantu Shah ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Lines ◽

Tumor Size ◽

Therapeutic Potential ◽

Mrna Translation ◽

Biological Role ◽

Loss Of Function

Abstract Abstract 833 A growing body of evidence suggests that the genome of a many organisms, particularly mammals is controlled not only by transcription factors but also by post-transcriptional programs that are modulated by the family of small RNA molecules including microRNAs (miRs). miRs can block mRNA translation and affect mRNA stability. We have evaluated profiles of 384 human miRs in CD138+ cells from 79 patients with multiple myeloma (MM), 11 MM cell lines and 9 healthy donors (HD) using qRT-PCR based microRNA array. This analysis has identified a MM specific miRNA signature that significantly correlates with OS (p=0.05) and EFS (p=0.017) of patients. Based on this signature one group of patients clustered with HD suggesting indolent disease while other with cell lines indicating aggressive disease. We identified significant modulation of expression of 61 microRNAs in MM cells compared to normal plasma cells. Specific miRs with established oncogenic and tumor suppressor functions such as miR-155, miR-585 and Let7-f were significantly dysregulated in MM (p<0.001). Modulation of miRs-155, -585 and Let7 were observed most frequently in the group of patients with poor OS and EFS suggesting their crucial role in MM. However biological role of these miRs have not yet been defined. To further evaluate biological function of these most recurrent miRs in MM, we evaluated role of miR-155, let-7f and mir-585 in MM cell lines by gain- and loss- of function experiments. We used locked nucleic acid (LNA) anti-miR probes for loss of function and pre-miR-155 for gain of function studies using them alone or in combination. Although manipulation of all 3 miRs induced 20-25% change in MM cell proliferation and/or induction of apoptosis, combination of anti-miR-let7f with pre-miR-155, and anti-miR-585 in combination with miR-155 had dramatic effects on MM cell proliferation and over 60% cells undergoing apoptosis. To evaluate the targets of these miRs, we have determined effects of these anti-miRs and pre-miR on global gene and miR expression profile in MM alone and in combinations. This analysis identified modulation of cluster of miRs as well as genes critical for cell growth and survival. Next, we have tested efficacy of these miRs in vivo in murine Xenograft model to evaluate their therapeutic potential. Tumor-bearing mice were treated intraperitoneal for four consecutively days with the LNA anti-miR-585 and Let-7 and pre-miR-155 probes and respective controls alone and in combination. We observed that the single LNA anti-miR-585 and let 7 and pre miR-155 treatment reduced tumor size by 36%, 31% and 155% in animal 7 days after treatment. However, significant tumor size reductions were achieved when animals were treated with combinations; anti-miR-Let 7f plus pre-miR-155 (58 %); LNA anti-miR-Let 7f plus LNA anti-miR-585 (56 %); LNA-anti-miR-585 plus pre-miR-155 (74 %).We did not observe any significant systemic toxicity in the animals. In conclusion our results suggest significant biological role for miR-585, let 7f and miR-155 in myeloma, both in vitro and in vivo; it highlights for the first time a concerted activity of combination of miRs and holds a great promise for developing novel therapeutic approach for myeloma. Disclosures: No relevant conflicts of interest to declare.

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Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

10.1101/711812 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ana M. Moreno ◽

Glaucilene F. Catroli ◽

Fernando Alemán ◽

Andrew Pla ◽

Sarah A. Woller ◽

...

Keyword(s):

Chronic Pain ◽

Genome Engineering ◽

Therapeutic Potential ◽

Sequence Similarity ◽

Thermal Hyperalgesia ◽

Loss Of Function ◽

High Sequence Similarity ◽

Inflammatory State

ABSTRACTCurrent treatments for chronic pain rely largely on opioids despite their unwanted side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing, with the voltage-gated sodium channel, NaV1.7 (SCN9A), being perhaps the most promising candidate for analgesic drug development. Specifically, a hereditary loss-of-function mutation in NaV1.7 leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence similarity between NaVsubtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of NaV1.7 via genome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins as a potential treatment for chronic pain. Towards this end, we first optimized the efficiency of NaV1.7 repressionin vitroin Neuro2A cells, and then by the lumbar intrathecal route delivered both genome-engineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain and BzATP-induced pain. Our results demonstrate: one, effective repression of NaV1.7 in lumbar dorsal root ganglia; two, reduced thermal hyperalgesia in the inflammatory state; three, decreased tactile allodynia in the neuropathic state; and four, no changes in normal motor function. We anticipate this genomically scarless and non-addictivepainamelioration approach enablingLong-lastingAnalgesia viaTargetedin vivoEpigeneticRepression of Nav1.7, a methodology we dubpain LATER, will have significant therapeutic potential, such as for preemptive administration in anticipation of a pain stimulus (pre-operatively), or during an established chronic pain state.One sentence summaryIn situepigenome engineering approach for genomically scarless, durable, and non-addictive management of pain.

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DDIS-33. SELECTIVE AND COMPLETE INHIBITION OF mTORC1 BY BI-STERIC mTOR INHIBITORS DRIVES THERAPEUTIC RESPONSE IN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.284 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi70-vi70

Author(s):

Qi Wen Fan ◽

Edward Lorenzana ◽

Xujun Luo ◽

Robin Lea ◽

Ozlem Aksoy ◽

...

Keyword(s):

Therapeutic Potential ◽

Mtor Inhibitors ◽

New Drugs ◽

Preclinical Model ◽

Selective Inhibitors ◽

Oncogenic Signaling ◽

Central Target ◽

Mtorc1 Signaling

Abstract Activation of phosphatidylinositol 3-kinase (PI3K)/PTEN pathway and oncogenic signaling via the mechanistic target of rapamycin (mTOR) occur in a majority of high-grade glial brain tumors. Allosteric mTOR inhibitors, such as rapamycin and other rapalogs, incompletely block mTORC1 by reducing phosphorylation of some substrates, including S6K1, but not 4EBP1. In contrast, ATP-competitive inhibitors, such as sapanisertib, fully inhibit mTORC1. However these inhibitors are also active against mTORC2 and lipid kinases, likely enhancing toxicity. A new class of selective mTORC1 inhibitor that interacts with both the ATP- and FKBP12/FRB-binding sites has been developed, which we term ‘bi-steric’. The prototype bi-steric inhibitor, RapaLink-1, blocks phosphorylation of many mTORC1 substrates, including 4EBP1. Importantly, RapaLink-1 showed improved efficacy in glioblastoma models in vivo as compared to rapamycin or sapanisertib (Fan et al., Cancer Cell 2017). Revolution Medicines has developed novel next-generation bi-steric mTORC1-selective inhibitors that exhibit potent and selective (>10-fold) inhibition of mTORC1 over mTORC2 in vitro in cell line models. Two of these compounds, RM-001 and RM-006, showed sustained blockade of mTORC1 signaling, including dephosphorylation of 4EBP1, following weekly ip dosing in an orthotopic U87MG-Luc model of glioblastoma. Repeated weekly administration of these agents resulted in significantly greater anti-tumor efficacy, as assessed via tumor burden (bioluminescence imaging) and overall survival in comparison to daily sapanisertib and the rapalog everolimus, and weekly dosing of the first generation bi-steric RapaLink-1, all at maximally tolerated doses. In summary, our data demonstrate that bi-steric mTORC1 selective inhibitors elict marked anti-tumor efficacy at doses that are well tolerated in a preclinical model of glioblastoma. Our study emphasizes the importance of mTOR as a central target in glioblastoma, and showcases the therapeutic potential of novel and selective clinical bi-steric mTORC1 inhibitors under development as investigational new drugs.

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Engineered Lactobacillus paracasei Producing Palmitoylethanolamide (PEA) Prevents Colitis in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22062945 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2945

Author(s):

Giuseppe Esposito ◽

Marcella Pesce ◽

Luisa Seguella ◽

Jie Lu ◽

Chiara Corpetti ◽

...

Keyword(s):

Intestinal Inflammation ◽

Therapeutic Potential ◽

Neutrophil Infiltration ◽

Lactobacillus Paracasei ◽

Stress Markers ◽

Intestinal Delivery ◽

Significant Amelioration ◽

Inflammatory Bowel

Palmitoylethanolamide (PEA) is an N-acylethanolamide produced on-demand by the enzyme N-acylphosphatidylethanolamine-preferring phospholipase D (NAPE-PLD). Being a key member of the larger family of bioactive autacoid local injury antagonist amides (ALIAmides), PEA significantly improves the clinical and histopathological stigmata in models of ulcerative colitis (UC). Despite its safety profile, high PEA doses are required in vivo to exert its therapeutic activity; therefore, PEA has been tested only in animals or human biopsy samples, to date. To overcome these limitations, we developed an NAPE-PLD-expressing Lactobacillus paracasei F19 (pNAPE-LP), able to produce PEA under the boost of ultra-low palmitate supply, and investigated its therapeutic potential in a murine model of UC. The coadministration of pNAPE-LP and palmitate led to a time-dependent release of PEA, resulting in a significant amelioration of the clinical and histological damage score, with a significantly reduced neutrophil infiltration, lower expression and release of pro-inflammatory cytokines and oxidative stress markers, and a markedly improved epithelial barrier integrity. We concluded that pNAPE-LP with ultra-low palmitate supply stands as a new method to increase the in situ intestinal delivery of PEA and as a new therapeutic able of controlling intestinal inflammation in inflammatory bowel disease.

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New Class of Anti-Inflammatory Therapeutics Based on Gold (III) Complexes in Intestinal Inflammation–Proof of Concept Based on In Vitro and In Vivo Studies

International Journal of Molecular Sciences ◽

10.3390/ijms22063121 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3121

Author(s):

Julia B. Krajewska ◽

Jakub Włodarczyk ◽

Damian Jacenik ◽

Radzisław Kordek ◽

Przemysław Taciak ◽

...

Keyword(s):

Mouse Model ◽

Intestinal Inflammation ◽

Therapeutic Potential ◽

Gastrointestinal Diseases ◽

Neutral Red ◽

Water Soluble ◽

In Vivo Studies ◽

Anti Inflammatory

Inflammatory bowel diseases (IBD) are at the top of the worldwide rankings for gastrointestinal diseases as regards occurrence, yet efficient and side-effect-free treatments are currently unavailable. In the current study, we proposed a new concept for anti-inflammatory treatment based on gold (III) complexes. A new gold (III) complex TGS 121 was designed and screened in the in vitro studies using a mouse macrophage cell line, RAW264.7, and in vivo, in the dextran sulphate sodium (DSS)-induced mouse model of colitis. Physicochemical studies showed that TGS 121 was highly water-soluble; it was stable in water, blood, and lymph, and impervious to sunlight. In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, the complex showed a potent anti-inflammatory profile, as evidenced in neutral red uptake and Griess tests. In the DSS-induced mouse model of colitis, the complex administered in two doses (1.68 μg/kg, intragastrically, and 16.8 μg/kg, intragastrically, once daily) produced a significant (* p < 0.05) anti-inflammatory effect, as shown by macroscopic score. The mechanism of action of TGS 121 was related to the enzymatic and non-enzymatic antioxidant system; moreover, TGS 121 induced changes in the tight junction complexes expression in the intestinal wall. This is the first study proving that gold (III) complexes may have therapeutic potential in the treatment of IBD.

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Modulation of mutantKrasG12D-driven lung tumorigenesisin vivoby gain or loss of PCDH7 function

10.1101/343103 ◽

2018 ◽

Author(s):

Xiaorong Zhou ◽

Bret M. Evers ◽

Mahesh S. Padanad ◽

James A. Richardson ◽

Emily Stein ◽

...

Keyword(s):

Lung Cancer ◽

Cell Surface ◽

Therapeutic Potential ◽

Surface Protein ◽

Experimental System ◽

Loss Of Function ◽

Lung Tumorigenesis ◽

Somatic Genome ◽

Tumor Types

ABSTRACTPROTOCADHERIN 7 (PCDH7), a transmembrane receptor and member of the Cadherin superfamily, is frequently overexpressed in lung adenocarcinoma and is associated with poor clinical outcome. While PCDH7 was recently shown to promote transformation and facilitate brain metastasis in lung and breast cancers, decreased PCDH7 expression has also been documented in colorectal, gastric, and invasive bladder cancers. These data suggest context-dependent functions for PCDH7 in distinct tumor types. Given that PCDH7 is a potentially targetable molecule on the surface of cancer cells, further investigation of its role in tumorigenesisin vivois needed to evaluate the therapeutic potential of its inhibition. Here we report the analysis of novel PCDH7 gain- and loss-of-function mouse models and provide compelling evidence that this cell-surface protein acts as a potent lung cancer driver. Employing a Cre-inducible transgenic allele, we demonstrated that enforced PCDH7 expression significantly acceleratesKrasG12D-driven lung tumorigenesis and potentiates MAPK pathway activation. Furthermore, we performedin vivosomatic genome editing with CRISPR/Cas9 inKrasLSL-G12D;Tp53fl/fl(KP) mice to assess the consequences of PCDH7 loss of function. Inactivation of PCDH7 in KP mice significantly reduced lung tumor development, prolonged survival, and diminished phospho-activation of ERK1/2. Together, these findings establish a critical oncogenic function for PCDH7in vivoand highlight the therapeutic potential of PCDH7 inhibition for lung cancer. Moreover, given recent reports of elevated or reduced PCDH7 in distinct tumor types, the new inducible transgenic model described here provides a robust experimental system for broadly elucidating the effects of PCDH7 overexpressionin vivo.AUTHOR SUMMARYLung cancer is the leading cause of cancer-associated deaths worldwide. PROTOCADHERIN 7 (PCDH7), cell surface protein and member of the Cadherin superfamily, is frequently overexpressed in lung adenocarcinomas and is associated with poor clinical outcome. Nevertheless, it has yet to be shownin vivowhether PCDH7 plays a role in the initiation and progression of lung cancer, and whether it represents an actionable therapeutic target. Here we demonstrate, using a novel transgenic mouse model, that PCDH7 overexpression acceleratesKrasG12D-driven lung tumorigenesis. Furthermore, we validate PCDH7 as a therapeutic target by knocking it out usingin vivosomatic genome editing in theKrasLSL-G12D;Tp53fl/fl(KP) model. Our results provide new insight into the mechanisms that drive lung cancer pathogenesis and, because targeting oncogenic cell-surface proteins with antibodies has proven to be a highly effective anti-cancer therapeutic strategy, establish a new target for cancer treatment. Moreover, given recent reports of elevated or reduced PCDH7 in distinct tumor types, the transgenic PCDH7 model described here provides a robust experimental system for elucidating the effects of PCDH7 overexpression in differentin vivosettings. This model will also provide an ideal system for future testing of therapeutics directed at PCDH7.

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PIEZO2 mediates injury-induced tactile pain in mice and humans

Science Translational Medicine ◽

10.1126/scitranslmed.aat9892 ◽

2018 ◽

Vol 10 (462) ◽

pp. eaat9892 ◽

Cited By ~ 55

Author(s):

Marcin Szczot ◽

Jaquette Liljencrantz ◽

Nima Ghitani ◽

Arnab Barik ◽

Ruby Lam ◽

...

Keyword(s):

Ion Channel ◽

Tissue Injury ◽

Skin Inflammation ◽

Tactile Allodynia ◽

Mechanical Stimuli ◽

Loss Of Function ◽

Inflammatory Conditions ◽

Touch Perception

Tissue injury and inflammation markedly alter touch perception, making normally innocuous sensations become intensely painful. Although this sensory distortion, known as tactile allodynia, is one of the most common types of pain, the mechanism by which gentle mechanical stimulation becomes unpleasant remains enigmatic. The stretch-gated ion channel PIEZO2 has been shown to mediate light touch, vibration detection, and proprioception. However, the role of this ion channel in nociception and pain has not been resolved. Here, we examined the importance of Piezo2 in the cellular representation of mechanosensation using in vivo imaging in mice. Piezo2-knockout neurons were completely insensitive to gentle dynamic touch but still responded robustly to noxious pinch. During inflammation and after injury, Piezo2 remained essential for detection of gentle mechanical stimuli. We hypothesized that loss of PIEZO2 might eliminate tactile allodynia in humans. Our results show that individuals with loss-of-function mutations in PIEZO2 completely failed to develop sensitization and painful reactions to touch after skin inflammation. These findings provide insight into the basis for tactile allodynia, identify the PIEZO2 mechanoreceptor as an essential mediator of touch under inflammatory conditions, and suggest that this ion channel might be targeted for treating tactile allodynia.

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Discovery of a CNS penetrant small molecule SMN2 splicing modulator with improved tolerability for spinal muscular atrophy

Scientific Reports ◽

10.1038/s41598-020-74346-9 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Shiori Ando ◽

Shunya Suzuki ◽

Shoichi Okubo ◽

Kazuki Ohuchi ◽

Kei Takahashi ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Small Molecule ◽

Therapeutic Potential ◽

Muscular Atrophy ◽

Survival Motor Neuron ◽

Tolerability Profile ◽

Loss Of Function ◽

Cryptic Exon

Abstract Spinal muscular atrophy (SMA) is a motor neuron disease, typically resulting from loss-of-function mutations in the survival motor neuron 1 (SMN1) gene. Nusinersen/SPINRAZA, a splice-switching oligonucleotide that modulates SMN2 (a paralog of SMN1) splicing and consequently increases SMN protein levels, has a therapeutic effect for SMA. Previously reported small-molecule SMN2 splicing modulators such as risdiplam/EVRYSDI and its analog SMN-C3 modulate not only the splicing of SMN2 but also that of secondary splice targets, including forkhead box protein M1 (FOXM1). Through screening SMA patient-derived fibroblasts, a novel small molecule, designated TEC-1, was identified that selectively modulates SMN2 splicing over three secondary splice targets. TEC-1 did not strongly affect the splicing of FOXM1, and unlike risdiplam, did not induce micronucleus formation. In addition, TEC-1 showed higher selectively on galactosylceramidase and huntingtin gene expression compared to previously reported compounds (e.g., SMN-C3) due to off-target effects on cryptic exon inclusion and nonsense-mediated mRNA decay. Moreover, TEC-1 significantly ameliorated the disease phenotype in an SMA murine model in vivo. Thus, TEC-1 may have promising therapeutic potential for SMA, and our study demonstrates the feasibility of RNA-targeting small-molecule drug development with an improved tolerability profile.

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In vivo genetic screen identifies a SLC5A3-dependent myo-inositol auxotrophy in acute myeloid leukemia

10.1101/2020.12.22.424018 ◽

2020 ◽

Author(s):

Yiliang Wei ◽

Shruti V. Iyer ◽

Ana S. H. Costa ◽

Zhaolin Yang ◽

Melissa Kramer ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Therapeutic Potential ◽

Genetic Interaction ◽

Synthetic Lethality ◽

Transcriptional Silencing ◽

Loss Of Function ◽

Dna Hypermethylation ◽

Acute Myeloid

AbstractAn enhanced requirement for extracellular nutrients is a hallmark property of cancer cells. Here, we optimized an in vivo genetic screening strategy for evaluating dependencies in acute myeloid leukemia (AML), which led to the identification of the myo-inositol transporter SLC5A3 as a unique vulnerability in this disease. In accord with this transport function, we demonstrate that the SLC5A3 dependency reflects a myo-inositol auxotrophy in AML. Importantly, the commonality among SLC5A3-dependent AML lines is the transcriptional silencing of ISYNA1, which encodes the rate limiting enzyme for myoinositol biosynthesis, inositol-3-phosphate synthase 1. We used gain- and loss-of-function experiments to demonstrate a synthetic lethal genetic interaction between ISYNA1 and SLC5A3 in AML, which function redundantly to sustain intracellular myo-inositol. Transcriptional silencing and DNA hypermethylation of ISYNA1 occur in a recurrent manner in human AML patient samples, in association with the presence of IDH1/IDH2 and CEBPA mutations. Collectively, our findings reveal myo-inositol auxotrophy as a novel form of metabolic dysregulation in AML, which is caused by the aberrant silencing of a biosynthetic enzyme.Statement of significanceHere, we show how epigenetic silencing can provoke a nutrient dependency in AML by exploiting a synthetic lethality relationship between biosynthesis and transport of myo-inositol. Blocking the function of this solute carrier may have therapeutic potential in an epigenetically-defined subset of AML.

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