Cerebral haemangioma is a disease that seriously endangers the safety of human life. The law of its occurrence, development, and prognosis is still not completely clear. Therefore, it has attracted ...the attention of many researchers at home and abroad in recent years. In response to the above problems, based on the original CT data of cerebral aneurysm in patients with intracranial aneurysms, the article reconstructs the cerebral haemangioma model through Autodesk remake 3D reconstruction software. And the finite element analysis software ANSYS CFD was used to establish the reconstructed finite element model of cerebral haemangioma. Hemodynamic analysis of the model was performed to obtain the distribution and change of velocity vector of blood flow field and pressure of blood vessel wall in the model of brain haemangioma. To investigate the hemodynamic mechanism of the formation, development and rupture of cerebral haemangioma and provide theoretical basis for clinical treatment.
Adenosine deaminase acting on RNA1 (ADAR1) preserves genomic integrity by preventing retroviral integration and retrotransposition during stress responses. However, ...inflammatory-microenvironment-induced ADAR1p110 to p150 splice isoform switching drives cancer stem cell (CSC) generation and therapeutic resistance in 20 malignancies. Previously, predicting and preventing ADAR1p150-mediated malignant RNA editing represented a significant challenge. Thus, we developed lentiviral ADAR1 and splicing reporters for non-invasive detection of splicing-mediated ADAR1 adenosine-to-inosine (A-to-I) RNA editing activation; a quantitative ADAR1p150 intracellular flow cytometric assay; a selective small-molecule inhibitor of splicing-mediated ADAR1 activation, Rebecsinib, which inhibits leukemia stem cell (LSC) self-renewal and prolongs humanized LSC mouse model survival at doses that spare normal hematopoietic stem and progenitor cells (HSPCs); and pre-IND studies showing favorable Rebecsinib toxicokinetic and pharmacodynamic (TK/PD) properties. Together, these results lay the foundation for developing Rebecsinib as a clinical ADAR1p150 antagonist aimed at obviating malignant microenvironment-driven LSC generation.
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•ADAR1p150 isoform-mediated A-to-I RNA editing fuels human LSC generation•Lentiviral ADAR1 and splicing reporters enable detection of ADAR1p150 activation•Rebecsinib inhibits ADAR1p150-driven LSC self-renewal while sparing normal HSCs•Rebecsinib pre-IND studies show scalable chemistry and favorable pharmacokinetics
Jamieson and colleagues demonstrate that splicing-mediated activation of the inflammation-responsive RNA editase ADAR1 can be inhibited by Rebecsinib, a selective splicing modulator with favorable safety, pharmacokinetic, and pharmacodynamic properties in pre-IND studies. These findings support Rebecsinib development as a potent ADAR1p150 antagonist aimed at preventing leukemia stem cell generation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Compelling murine studies demonstrate that adenosine-to-inosine (A-to-I) RNA editing mediated by adenosine deaminase associated with RNA1 (ADAR1) is vital for both fetal and adult ...hematopoiesis. While genetic ablation of ADAR1 leads to murine embryonic lethality due to severe defects in erythropoiesis, conditional deletion in the hematopoietic system impairs maintenance indicative of cell type and context specific roles for ADAR1 in cell fate specification and self-renewal. By regulating mRNA and microRNA (miRNA) stability, ADAR1 exhibit wide-ranging effects on embryonic development and stem cell regulation. We have previously shown that inflammation-responsive ADAR1 plays important roles in both stem cell differentiation and self-renewal in CML (chronic myeloid leukemia) disease progression. Here, we describe a novel function of ADAR1 in cell cycle regulation of normal hematopoietic stem cell and progenitors (HSPC) by regulation of miRNA biogenesis.
Our results demonstrated that ADAR1 induces G0 to G1 phase transition in normal cord blood HSPCs, as demonstrated by elevated expression of Ki67, reduced DiR signal, and enhanced in vivo cord blood engraftment. Cell cycle qRT-qPCR microarray of 84 cell cycle transcripts and whole transcriptome RNA-sequencing analysis of KEGG cell cycle pathway indicate that several cell cycle genes are differentially expression upon overexpression of ADAR1 WT or an A-to-I editing deficient ADAR1 mutant (ADAR1E912A). We previously demonstrated that impaired biogenesis of let-7 miRNAs by ADAR1 WT induces enhanced self-renewal in cord blood CD34+ HSPCs. To determine the miRNA targets of ADAR1-mediated RNA editing, we performed miRNome miScript PCR array of 1008 miRNA candidates in cord blood CD34+ HSPCs overexpressing ADAR1 WT or ADAR1E912A. Total of 263 miRNAs were differentially expressed (142 upregulated and 121 downregulated) by comparing ADAR1 WT to the backbone control. Interestingly, ADAR1E912A mutant also exhibit A-to-I editing independent regulation of miRNAs (307 upregulated and 59 downregulated). We found that the expression of miR-26a-5p, a miRNA frequently downregulated in leukemia, is inhibited by ADAR1-mediated RNA editing. ADAR1 directly binds and edits the DROSHA cleavage site of primary miR-26a transcript, thereby prevent miR26a-5p maturation. Moreover, lentiviral expression of mature miR26-5p reverses the effect of ADAR1 WT, including enhanced CDKN1A expression, inhibition of cord blood proliferation in vivo, as well as reduced HSC self-renewal as measured by colony-formation assay.
Our finding suggests carefully regulated A-to-I editing by ADAR1 is essential for the maintenance of proper cell proliferation in HSC. For future study, it will be interesting to investigate if the elevated expression of ADAR1 in CML BC LSC contributes to false regulation of cell cycle that leads to the expansion of malignant leukemia stem cells.
Citation Format: Qingfei Jiang, Maria Anna Zipeto, Nathan Delos Santos, Sheldon Morris, Catriona Jamieson. RNA editing enzyme ADAR1 accelerates normal hematopoiesis cell cycle by regulation microRNA biogenesis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 299. doi:10.1158/1538-7445.AM2017-299
Cell survival and genome rescue after UV irradiation in Escherichia coli depends on DNA repair mechanisms induced in response to DNA damage as part of the SOS regulon. SOS occurs in two phases. The ...first phase is dominated by accurate repair processes such as excision and recombinational DNA repair, while the second phase is characterized by a large approximately 100-fold increase in mutations caused by an error-prone replication of damaged DNA templates. SOS mutagenesis occurs as a direct result of the action of the UmuDC gene-products, which form the low fidelity Escherichia coli DNA polymerase V, a heterotrimeric complex composed of UmuD'(2)C. This chapter describes the preparation of highly purified native pol V that is suitable for a wide range of biochemical studies of protein-protein, protein-DNA interactions and translesion-synthesis (TLS) mechanisms.
BACKGROUND
Clonal stem cell derived myeloproliferative neoplasms (MPNs) have a propensity to evolve to acute myeloid leukemia (AML). Deregulation of the innate immune deaminase associated with RNA1 ...(ADAR1) has been linked to malignant progression and therapeutic resistance. Increased expression of the stem cell gene, human telomerase reverse transcriptase (hTERT), has also been linked with malignant transformation. However, the combinatorial role of ADAR1 and hTERT in the evolution of MPN stem cells to therapy resistant acute myeloid leukemia stem cells (LSCs) and the capacity of a telomerase inhibitor, imetelstat, to prevent survival and self-renewal of pre-LSC and LSC had not been established. Recent clinical trials show early signs of efficacy of imetelstat in treatment of myelofibrosis (MF). However, its role in selectively inhibiting pre-LSC transformation to self-renewing LSC has not been elucidated. Here we show that targeting telomerase activity prevents pre-LSC and LSC maintenance both in vitro and in vivo, suggesting telomerase inhibition as an effective strategy for preventing MPN progression.
METHODS
To quantify hTERT level and ADAR1 activity in the setting of normal HSPC and MPN stem cell evolution, whole genome sequencing (WGS) analysis was performed on 76 normal and MPN blood CD34+ cells and matching saliva samples. Results were compared with RNA-seq of 100 FACS purified young, aged, MPN and AML CD34+CD38- stem cells and CD34+CD38+ progenitor cells. Confocal fluorescence microscopic evaluation of stem cell ADAR1 and hTERT localization, telomere length by Flow-FISH and telomerase activity by TRAP assays, lentiviral ADAR1 overexpression and shRNA knockdown were performed. In vitro stromal co-cultures, and humanized immunocompromised mouse models were established to determine the impact of imetelstat (a oligonucleotide inhibitor of telomerase) on normal, MPN stem cell and LSC maintenance.
RESULTS
Combined hTERT overexpression, ADAR1 activation and a significant reduction in telomere length correlated with accelerated stem cell aging during MPN progression to AML. Increased ADAR1 mediated adenosine to inosine (A-to-I) transcript editing coincided with accelerated telomere shortening in high risk MPN stem cells. Moreover, lentiviral ADAR1 overexpression enhanced pre-LSC engraftment. Treatment with imetelstat reduced MPN stem cell and LSC propagation in stromal co-cultures as well as in humanized mouse models commensurate with reduced hTERT expression levels and telomerase activity and decreased ADAR1 editing activity. Specifically, stromal co-culture assays revealed that combined treatment with dasatinib at 1 nM, and imetelstat at 1 µM or 5 µM significantly inhibited survival and replating of blast crisis (BC) CML progenitors compared with aged bone marrow progenitors (p < 0.001, ANOVA). As a single agent, imetelstat (5 µM) inhibited survival and replating of pre-LSC derived from myelofibrosis compared with normal bone marrow progenitor samples (p < 0.001, ANOVA). In pre-LSC MPN NSG-SGM mouse models established from 4 different MF samples, a significant reduction in proliferation of human CD45+ cells (p < 0.01, t test) was observed in bone marrow and spleen, when compared with vehicle control. Treatment of humanized LSC mouse models, established with 5 different BC CML, with 30 mg/kg of imetelstat, 3 times a week for 4 weeks resulted in a significant reduction in proliferation of malignant progenitors and human CD45+ cells (p < 0.001, ANOVA). As measured by a Flow-FISH assay, abnormal telomere length was reversed by imetelstat treatment compared with mismatch control (p < 0.05, ANOVA). In addition, FACS analysis revealed a significant reduction in activated beta-catenin expression after imetelstat treatment of LSC engrafted mice compared with vehicle control (p < 0.01, ANOVA). Finally, RNA-seq analysis performed on human CD34+ cells from imetelstat treated LSC mouse models revealed a significant reduction in LSC harboring malignant ADAR1-mediated A-to-I editing at doses that spared normal hematopoietic stem cells.
CONCLUSIONS
Combined WGS and RNA-Seq analyses, lentiviral ADAR1 overexpression, stromal co-culture assays and humanized pre-LSC and LSC mouse model studies reveal that pre-LSC evolution into LSC coincides with both ADAR1 and hTERT activation, which can be prevented with imetelstat.
Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Jamieson:Forty Seven Inc: Patents & Royalties; Bristol-Myers Squibb: Other.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Compelling murine studies demonstrate that adenosine-to-inosine (A-to-I) RNA editing mediated by adenosine deaminase associated with RNA1 (ADAR1) is vital for both fetal and adult hematopoiesis. ...While genetic ablation of ADAR1 editase leads to murine embryonic lethality due to severe defects in erythropoiesis, conditional deletion in the hematopoietic system impairs maintenance indicative of cell type and context specific roles for ADAR1 in cell fate specification and self-renewal. By regulating mRNA and microRNA (miRNA) stability, ADAR1 exhibit wide-ranging effects on embryonic development and stem cell regulation. We have previously shown that inflammation-responsive ADAR1 plays important roles in both stem cell differentiation and self-renewal in CML (chronic myeloid leukemia) disease progression. Here, we describe a novel function of ADAR1 in cell cycle regulation of normal hematopoietic stem cell and progenitors (HSPC) by regulation of miRNA biogenesis.
Our results demonstrated that ADAR1 induces G0 to G1 phase transition in normal cord blood HSPCs, as demonstrated by elevated expression of Ki67, reduced DiR signal, and enhanced in vivo cord blood engraftment. Cell cycle qRT-qPCR microarray of 84 cell cycle transcripts and whole transcriptome RNA-sequencing analysis of KEGG cell cycle pathway indicate that several cell cycle genes (CDKN1A, CDKN2A, CCNC, CCND1, BRCA2, etc) are differentially expression upon overexpression of ADAR1 WT or an A-to-I editing deficient ADAR1 mutant (ADAR1E912A). We previously demonstrated that impaired biogenesis of let-7 miRNAs by ADAR1 WT induces enhanced self-renewal in cord blood CD34+ HSPCs. To determine the miRNA targets of ADAR1-mediated RNA editing, we performed miRNome miScript PCR array of 1008 miRNA candidates in cord blood CD34+ HSPCs overexpressing ADAR1 WT or ADAR1E912A. Total of 263 miRNAs were differentially expressed (142 upregulated and 121 downregulated) by comparing ADAR1 WT to the backbone control. Interestingly, ADAR1E912A mutant also exhibit A-to-I editing independent regulation of miRNAs (307 upregulated and 59 downregulated). We found that the expression of miR-26a-5p, a miRNA frequently downregulated in leukemia, is inhibited by ADAR1-mediated RNA editing. ADAR1 directly binds and edits the DROSHA cleavage site of primary miR-26a transcript, thereby prevent miR26a-5p maturation. Moreover, lentiviral expression of mature miR26-5p reverses the effect of ADAR1 WT, including enhanced CDKN1A expression, inhibition of cord blood proliferation in vivo, as well as reduced HSC self-renewal as measured by colony-formation assay.
Our finding suggests carefully regulated A-to-I editing by ADAR1 is essential for the maintenance of proper cell proliferation in HSC. For future study, it will be interesting to investigate if the elevated expression of ADAR1 in CML BC LSC contributes to false regulation of cell cycle that leads to the expansion of malignant leukemia stem cells.
Jamieson:CTI Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
While inflammation induced ADAR1 RNA deaminases protect the human genome from retroviral integration, deregulation promotes therapeutic resistance in many malignancies. However, the ...combinatorial role of these deaminases in pre-leukemia stem cell (pre-LSC) evolution to therapy resistant LSC had not been elucidated. Thus, we performed whole genome sequencing (WGS) analysis of 43 CD34+pre-leukemic myeloproliferative neoplasm (MPN) samples compared with matched saliva and non-MPN controls andwhole transcriptome sequencing (RNA-seq) analysis of 113 FACS-purified hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC) from MPN, acute myeloid leukemia (AML) and healthy young and aged samples. During MPN progression, inflammation-driven ADAR1 isoform p150 upregulation corresponded with increased Adenosine-to-Inosine (A-to-I) transitions in both MPN stem and progenitor populations. We identified unique A-to-I editing events in coding regions that are associated with either normal stem progenitors or with MPN progenitors. In addition, STAT3 transcript hyper-editing leads to STAT3beta splice isoform expression. Moreover, lentiviral ADAR1p150 overexpression enhanced replating as well as beta-catenin activation, which was reversed by lentiviral shRNA ADAR1 knockdown. In summary, innate immune deaminase deregulation fuels pre-LSC evolution to LSC and may represent a vital LSC therapeutic vulnerability.
Citation Format: Qingfei Jiang, Frida Holm, Jane Isquith, Adam Mark, Cayla Mason, Eduardo Reynoso, Isabella Morris, Wenxue Ma, Raymond Diep, Jessica Pham, Chanond Nasamran, Guorong Xu, Roman Sasik, Sara Brin Rosenthal, Amanda Birmingham, Leslie Crews, Gabriel Pineda, Thomas Whisenant, Kathleen Fisch, Catriona Jamieson. A-to-I RNA deaminase deregulation in pre-leukemia stem cell evolution abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5726.
Abstract
Introduction: Myeloproliferative neoplasms (MPN) including blast crisis (BC) CML and myelofibrosis (MF) are characterized by the clonal proliferation of hematopoietic cell lineages, mostly ...in the marrow. BC CML gives rise to TKI resistant myeloid progenitors that activate Wnt/β-catenin signaling pathway. However, BCR-ABL TKI resistant BC CML exhibits a robust telomerase activity and presents at very low or undetectable level in normal cells, and telomerase plays a pivotal role in cancer cell growth and may serve as an ideal target for anticancer therapeutics. In addition, β-catenin had been reported to transcriptionally regulate human telomerase reverse transcriptase (TERT). Telomerase is composed of the enzymatic reverse transcriptase protein TERT and the RNA template TERC. Thus, we investigated the capacity of imetelstat, a telomerase inhibitor, which binds to the TERC subunit with high affinity to prevent self-renewal of malignant progenitors. Recent clinical trials showed early signs of efficacy in MF. But, it's role in selectively inhibiting leukemia stem cell (LSC) self-renewing in CML has not been elucidated.
Methods and Results: Progenitors from BC CML were compared with chronic phase (CP) CML and primary normal samples, RNA-seq results revealed upregulation of TERT suggesting a role for TERT activation in BC CML progenitor transformation. Human MPN progenitor co-culture experiments revealed that combined treatment with dasatinib at 1 nM, and imetelstat at 1 or 5 uM significantly inhibited (p < 0.001, ANOVA) in vitro replating of BC CML compared with aged bone marrow progenitors. Also, imetelstat (5 mM) significantly reduced replating of MF compared with normal progenitor samples. Treatment of humanized MPN mouse models, established with 5 different BC CML and 4 different MF samples, at 30 mg/kg of imetelstat, three times a week for 4 weeks resulted in a significant reduction of malignant progenitors and human CD45+ cells (p < 0.001, t test) in BC CML, and a significant reduction of human CD45+ cells (p<0.01, t test) in MF in both marrow and spleen, when compared with vehicle controls. FACS analysis revealed a significant reduction of activated β-catenin protein in BC CML engrafted human progenitors after imetelstat treatment (p < 0.01, t test) compared with vehicle control. In addition, a significant inhibition of TERT (p = 0.03) and TERC (p = 0.02) was observed in BC CML LSC isolated from imetelstat treated mouse marrow when compared with vehicle control. Notably, imetelstat treatment spares normal human cells in humanized normal stem cell mouse models. Recent RNA-sequencing analysis showed an increase in ADAR1 expression during MPN progression, and our RNA-seq analysis demonstrated a decreased ADAR1 gene expression (p < 0.005) as well as overall adenosine to inosine editing rates as measured by edits per million reads (p <0.005) following imetelstat treatment of BC CML engrafted mice when compared to mismatch control.
Conclusions: Niche responsive interactions between the telomerase complex and the Wnt/β-catenin self-renewal pathway sensitize β-catenin activated MPN progenitors to imetelstat treatment in both the in vitro co-culture and in vivo humanized MPN mouse models thereby providing a strong rationale for studies assessing eradication of malignant progenitors using imetelstat.
Citation Format: Wenxue Ma, Larisa Balaian, Cayla Mason, Raymond Diep, Jessica Pham, Qingfei Jiang, Jeremy Lee, Sheldon Morris, Phoebe Mondala, Ping Chen, Thomas Whisenant, Mary Donohoe, Benjamin Heyman, Edward Ball, Fei Huang, Catriona Jamieson. Imetelstat inhibits RNA-editing mediated myeloproliferative neoplasm stem cell self-renewal abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3792.
Recent studies demonstrate the importance of post-transcriptional adenosine-to-inosine (A-to-I) RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) in normal fetal and adult ...hematopoiesis. RNA-sequencing studies have shown that elevated levels of the ADAR1 editase has emerged as a dominant driver of cancer progression and therapeutic resistance. Specifically, the deregulation of ADAR1 promotes the transformation of chronic myeloid leukemia (CML) from chronic phase (CP) to a therapy resistant blast crisis (BC) phase. Through the regulation of mRNA and microRNA (miRNA) stability, ADAR1 plays a pivotal role in embryonic development and stem cell regulation. We have previously shown that inflammation-responsive ADAR1 heavily contributes to stem cell differentiation and self-renewal in CML disease progression. Here, we describe a novel role of ADAR1 in cell cycle regulation of BC leukemia cells through regulation of miRNA biogenesis.
To investigate the role of ADAR1 in miRNA regulation, we performed miRNome miScript PCR array analysis of 1008 miRNAs in cord blood CD34+ expressing hematopoietic stem and progenitor cells (HSPCs) overexpressing ADAR1 wild type (WT) and A-to-I editing deficient ADAR1 mutant. Overall, a total of 112 miRNAs were significantly differentially expressed following ADAR1 expression with cell cycle identified as the top cellular pathway significantly targeted by miRNAs regulated by ADAR1. Notably, ADAR1 editase activity inhibits the expression of miR-26a-5p, a tumor suppressor miRNA that is frequently downregulated in BC CML. ADAR1 inhibits miR-26a-5p through direct editing of the DROSHA cleavage site of primary miR-26a-5p, preventing miR-26a-5p maturation and processing. In normal hematopoietic progenitors, ADAR1-mediated inhibition of miR-26a results in repression of cyclin-dependent kinase inhibitor 1A (CDKN1A) expression indirectly via suppression of the polycomb repressive complex, enhancer of zeste homolog 2 (EZH2), thereby accelerating cell cycle transit. However, in BC CML progenitors, decreased EZH2 and increased CDKN1A oppose the cell cycle accelerating effect of ADAR1. Moreover, we found that the miR-26a targets a different set of mRNA in BC CML compared to cord blood HSPC and has divergent roles in cell cycle regulation. Lentiviral miR-26a overexpression reduced BC leukemia stem cell (LSC) dormancy in the bone marrow and reverses the functional effects of ADAR1, including inhibition of BC cell proliferation in vivo and impaired LSC self-renewal capacity as measured by colony forming assays.
Our finding reveals the effects of ADAR1 in LSC generation through impairing biogenesis of cell cycle regulatory miRNAs. The deregulation of ADAR1 contributes to the malignant reprogramming of progenitors into dormant LSCs that are resistant to therapeutic treatments. Future development of ADAR1 inhibitors may be effective in the elimination of dormant BC CML LSCs that evade tyrosine kinase inhibitors.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Innate immune anti-viral adenosine to inosine (A-to-I) base editing enzymes (editases) promote hematopoietic stem cell (HSC) self-renewal and protect the human genome from retroviral integration in ...response to inflammatory cytokine signaling. However, hyper-editing has been linked to therapeutic resistance and cancer progression. Because myeloproliferative neoplasm (MPN) progression is typified by increased JAK2/STAT-mediated cytokine signaling, we investigated the cell type and context specific role of adenosine deaminase acting on RNA1 (ADAR1) editaseactivity in MPN pre-leukemia stem cell (pre-LSC) evolution into acute myeloid leukemia stem cells (LSCs). Here we show by whole transcriptome sequencing (RNA-seq) of 113 FACS-purified hematopoietic stem cells and progenitors from 78 individuals, including 54 MPN and AML patients and 24healthy young and aged individuals, that anti-viral signaling pathway activation and splice isoform switching from ADAR1p110 to JAK2/STAT-inducible ADAR1p150 RNA editase activation contributes to MPN progression. Pre-LSC evolution to LSC was characterized by ADAR1p150 upregulation, distinctive RNA editome patterns, STAT3 hyper-editing, increased replating as a measure of self-renewal. Moreover, LSC generation was typified by beta-catenin self-renewal pathway upregulation, which was recapitulated by lentiviral ADAR1p150 overexpression and reversed by lentiviral ADAR1p150 shRNA knockdown. Our studyunderscores the importance of inflammatory-cytokine fueled enzymatic mutagenesis in human MPN pre-LSC evolution to LSC. Thus, this study sets the stage for developing predictive RNA editome biomarkers of LSC generation to guidetherapeutic strategies aimed at preventing progression of hematopoietic malignancies.
Crews:Ionis Pharmaceuticals: Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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