bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A032: Targeting RAS beyond KRAS, a review
Authors: Singh Neetu , Tyson Darren R. , Sarma Partha Pratim , Katike Sathish , Bhavar Prashant K. , Surampudi Uday Kumar
Published: May 2023

RAS proteins belong to the family of GTPases and plays instrumental role in cellular growth and proliferation and dysregulation of RAS signalling is one of the key drivers of tumorigenesis. The RAS protein has four isoforms namely KRAS4A, KRAS4B, NRAS and HRAS with amino acid codons 12, 13 and 61 as common hotspots for RAS mutations. Each of these hotspot mutations appears across several cancer types, however each of them have been noted to have specific distribution across different tissues. For example, mutations in codon 12 of KRAS are most common in pancreatic, lung and colorectal cancer, NRAS mutations affecting Q61 and G12 are most prevalent in melanoma and haematological malignancies, respectively, and HRAS mutations are more frequently altered in thyroid, bladder and head and neck cancers. Substantial efforts have been made to develop small molecule inhibitors targeting KRASG12C, with demonstrated success in clinic. Early success with KRASG12C has prompted researchers targeting other RAS isoforms, such as H-RAS and N-RAS to address RAS mutated cancer burden. Discovery of pan-RAS monobody that binds to all RAS isoforms have opened new opportunities. Development of small molecule inhibitors of RAS membrane association is gaining potential as a therapeutic strategy to curb RAS signalling; Lonafarnib and Tipifarnib, inhibitors of farnesyltransferase that lipidate Ras to facilitate membrane localization, have shown effectiveness in HRAS mutated cancers and are in active clinical evaluation. Although the lack of a hydrophobic binding pocket in NRAS poses challenges to drug targeting, specific strategies such as amphiphile-mediated depalmitoylation to target the post-translational modification of NRAS and reduce its activity are being investigated. The wide variety of approaches to target the RAS signalling pathway, beyond KRAS, have resulted in a broadening patent landscape. While finding ways to specifically target RAS mutants remains a daunting challenge, herculean efforts to make clinically useful RAS-targeted drugs are beginning to provide a bounty of weapons to fight against RAS-driven tumors.

Citation Format: Neetu Singh, Darren R. Tyson, Partha Pratim Sarma, Sathish Katike, Prashant K. Bhavar, Uday Kumar Surampudi. Targeting RAS beyond KRAS, a review [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A032.
Abstract B006: Novel direct RAS inhibitors for pancreatic cancer
Authors: Clarke Geoff , Arshad Tariq , Donninger Howard , von Baby Becca , Ferrill Rachel , Sabo Mike , Burlison Joe , Trent John
Published: May 2023

RAS oncogenes are frequently activated by mutations in pancreatic and lung cancer, where they appear to act as driving mutations. This study examines the activity of a series of novel direct RAS inhibitors with a predicted unique interaction region. We have used in silico library screening followed by Medicinal Chemistry optimization to develop the compounds. We have validated the agents using Microscale Thermophoresis to quantify binding to recombinant RAS protein as well as NMR analysis of the drug/RAS complex. We used 3D growth inhibition assays in mutant RAS cell lines and protein-based RAS signaling assays to quantify and characterize the action of the family of inhibitors. We have identified compounds that bind wild type K-RAS and H-RAS but exhibit preferential binding to the K-RAS-G12D and KRAS-G12C mutants. We can suppress the association of mutant RAS protein with its effector RAF-1 in treated cells. We also observe suppression of mutant RAS signaling and inhibition of 3D cell growth of mutant RAS cell lines with the agents. As the compound family are predicted to bind to a different site than either AMG-510 (K-RAS G12C specific) or MRTX-1133 (K-RAS G12D specific), agents we have also tested co-operative activity with these drugs. Our compounds enhanced the effects of MRTX-1133 against K-RAS G12D cells and had a similar effect on AMG-510 in K-RAS G12C cell lines. These agents may serve as novel anti-RAS therapeutics and may have potential to enhance the activity or suppress resistance to AMG-510 and MRTX-1133.

Citation Format: Geoff Clarke, Tariq Arshad, Howard Donninger, Becca von Baby, Rachel Ferrill, Mike Sabo, Joe Burlison, John Trent. Novel direct RAS inhibitors for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B006.
Abstract B012: Effects of adagrasib on oncogenic signaling, immune cell regulation and biomarkers of response in preliminary clinical analyses
Authors: Hallin Jill , Hover Laura , Fernandez-Benet Julio , Pavlicek Adam , Anderes Kenna , Jänne Pasi A. , Riely Gregory J. , Spira Alexander I. , Zhang Jun , Olson Peter , Christensen James G.
Published: May 2023

The recent approval of KRAS G12C inhibitors has provided novel treatment options for lung, colorectal and other cancer patients harboring this mutation and has changed the landscape of research for these cancers. Current priorities in the field include characterizing the mechanism of action of KRAS G12C inhibitors and the mechanisms underlying resistance to KRAS inhibition. Utilizing access to pre and post-treatment patient samples from KRYSTAL-1, preliminary gene expression analyses from baseline and post-adagrasib (Cycle 1, Day 8) treated patient samples demonstrated multiple oncogenic pathway gene signatures, including MYC, mTOR, cell cycle, EMT and inflammation-related signatures, were significantly regulated by adagrasib. KRAS/MAPK pathway and cell cycle-related genes including ETV4, CCND1, DUSP6, TOP1, and CENPA, as well as the Singh KRAS dependency signature were significantly downregulated in Cycle1, Day 8 compared to baseline tumor biopsies. Genes implicated in inflammation and the immune response were significantly upregulated in Cycle 1, Day 8 compared to baseline tumor biopsies. In agreement with the gene expression data as well as findings from syngeneic mouse models, preliminary immunohistochemical analysis on matched baseline, post-adagrasib treated (Cycle 1, Day 8), and end of treatment FFPE patient samples revealed marked changes in tumor cell mechanistic biomarkers and immune cell types following adagrasib treatment. These observations included decreased tumor Ki67 and increased tumor PD-L1, as well as marked alterations in tumor immune cell composition, including increased CD8+ T cells and decreased MDSCs following adagrasib treatment in several patients. Finally, flow cytometry and TCRb sequencing data from adagrasib and pembrolizumab-treated patient blood samples demonstrated an increase in several activated CD8+ T cell populations and the emergence of new T cell clones in a subset of patients after combination treatment. Together, these data suggest robust evaluation of patient biopsies pre and post adagrasib treatment may better predict outcomes that can be achieved in patients harboring KRASG12C mutant cancers and can guide early clinical development strategies, including support for combining adagrasib with immune checkpoint inhibitors.

Citation Format: Jill Hallin, Laura Hover, Julio Fernandez-Benet, Adam Pavlicek, Kenna Anderes, Pasi A. Jänne, Gregory J. Riely, Alexander I. Spira, Jun Zhang, Peter Olson, James G. Christensen. Effects of adagrasib on oncogenic signaling, immune cell regulation and biomarkers of response in preliminary clinical analyses [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B012.
Abstract IA11: Three-dimensional genomic mapping of human pancreatic tissue reveals striking multifocality and genetic heterogeneity in precancerous lesions
Authors: Wood Laura D.
Published: May 2023

Pancreatic intraepithelial neoplasia (PanIN) is a precursor to pancreatic cancer and represents a critical opportunity for cancer interception. However, the number, size, shape, and connectivity of PanINs in human pancreatic tissue samples are largely unknown. In this study, we quantitatively assessed human PanINs using CODA, a novel machine-learning pipeline for 3D image analysis that generates quantifiable models of large pieces of human pancreas with single-cell resolution. Using a cohort of 38 large slabs of grossly normal human pancreas from surgical resection specimens, we identified striking multifocality of PanINs, with a mean burden of 13 spatially separate PanINs per cm3 of sampled tissue. Extrapolating this burden to the entire pancreas suggested a median of approximately 1000 PanINs in an entire pancreas. In order to better understand the clonal relationships within and between PanINs, we developed a pipeline for CODA-guided multi-region genomic analysis of PanINs, including targeted and whole exome sequencing. Multi-region assessment of 37 PanINs from eight additional human pancreatic tissue slabs revealed that almost all PanINs contained hotspot mutations in the oncogene KRAS, but no gene other than KRAS was altered in more than 20% of the analyzed PanINs. PanINs contained a mean of 13 somatic mutations per region when analyzed by whole exome sequencing. The majority of analyzed PanINs originated from independent clonal events, with distinct somatic mutation profiles between PanINs in the same tissue slab. A subset of the analyzed PanINs contained multiple KRAS mutations, suggesting a polyclonal origin even in PanINs that are contiguous by rigorous 3D assessment. This study leverages a novel 3D genomic mapping approach to describe, for the first time, the spatial and genetic multifocality of human PanINs, providing important insights into the initiation and progression of pancreatic neoplasia.

Citation Format: Laura D. Wood. Three-dimensional genomic mapping of human pancreatic tissue reveals striking multifocality and genetic heterogeneity in precancerous lesions [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA11.
Abstract IA14: Host autophagy mediates organ wasting and nutrient mobilization for tumor growth
Authors: Holland Petter , Schoborg Todd Andrew , Abramovich Ifat , Takáts Szabolcs , Dillard Caroline , Jain Ashish , O'Farrell Fergal , Schultz Sebastian Wolfgang , Hagopian William M. , Quintana Eduardo Martin , Ng Rachel , Katheder Nadja Sandra , Rahman Mohammed Mahidur , Reis José Gerardo Teles , Brech Andreas , Jasper Heinrich , Rusan Nasser M. , Jahren Anne Hope , Gottlieb Eyal , Rusten Tor Erik
Published: May 2023

During tumor growth-when nutrient and anabolic demands are high-autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well-characterized malignant tumor model in Drosophila melanogaster. Micro-computed X-ray tomography and metabolic profiling reveal that RasV12 ; scrib-/- tumors grow 10-fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, -motility, -feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. Thus, host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.

Citation Format: Petter Holland, Todd Andrew Schoborg, Ifat Abramovich, Szabolcs Takáts, Caroline Dillard, Ashish Jain, Fergal O'Farrell, Sebastian Wolfgang Schultz, William M. Hagopian, Eduardo Martin Quintana, Rachel Ng, Nadja Sandra Katheder, Mohammed Mahidur Rahman, José Gerardo Teles Reis, Andreas Brech, Heinrich Jasper, Nasser M. Rusan, Anne Hope Jahren, Eyal Gottlieb, Tor Erik Rusten. Host autophagy mediates organ wasting and nutrient mobilization for tumor growth [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA14.
Abstract IA26: Exploiting altered metabolism as a therapeutic strategy for RAS-driven cancers
Authors: DeLiberty Jonathan M. , Robb Ryan , Gates Claire E. , Pieper Noah L. , Yang Runying , Stalnecker Clint A. , Bryant Kirsten L.
Published: May 2023

We recently determined that concurrent inhibition of autophagy, using the lysosomal inhibitor chloroquine (CQ), and of ERK, using a small molecule ERK inhibitor (ERKi), synergistically suppressed the growth of pancreatic ductal adenocarcinoma (PDAC) cell lines and patient xenograft-derived (PDX) organoids in vitro and PDX tumors in vivo (Bryant et al., 2019, Nat Med 25:628). Our findings, together with similar observations by McMahon, Kinsey and colleagues (Kinsey et al., 2019, Nat Med 25:620), provided the rationale for our initiation of Phase I and Phase I/II clinical trials evaluating the combination of MEKi (binimetinib; NCT04132505) or ERKi (LY3214996; NCT04386057) with hydroxychloroquine (HCQ) in PDAC. We have extended these findings and determined that combined inhibition of the ERK MAPK pathway and autophagy is effective in additional cancers driven by KRAS/NRAS, BRAF, or EGFR. Additionally, we have also shown that the combined inhibition of KRASG12C or KRASG12D and autophagy was effective in KRAS-mutant cancers. Our ongoing studies are centered on developing additional combinations for targeting metabolic resistance mechanisms to KRAS or ERK MAPK targerted therapies. First, we performed a CRISPR/Cas-9 mediated genetic loss-of-function screen in the presence of CQ to determine additional sensitizers as well as mediators of resistance to autophagy inhibition. Top sensitizers included multiple facilitators of the DNA damage response, mTOR pathway components, and genes involved in the upstream regulation of the autophagy pathway. Second, we determined that autophagic signaling is temporally regulated following RAS pathway inhibition and hypothesize that further dissection of this regulation will improve current anti-nutrient scavenging treatment strategies. We conclude that concurrent suppression of multiple metabolic processes, to block compensatory rebound activities, will be needed for effective PDAC treatment.

Citation Format: Jonathan M. DeLiberty, Ryan Robb, Claire E. Gates, Noah L. Pieper, Runying Yang, Clint A. Stalnecker, Kirsten L. Bryant. Exploiting altered metabolism as a therapeutic strategy for RAS-driven cancers [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA26.
Supplementary Table S5 from Validation of an Abridged Breast Cancer Risk Prediction Model for the General Population
Authors: Spaeth Erika L. , Dite Gillian S. , Hopper John L. , Allman Richard
Published: May 2023

Supplementary Table S5 shows the five-year vs full-lifetime risk classification for 313-SNP BRISK for unaffected and affected women
Supplementary Table S4 from Validation of an Abridged Breast Cancer Risk Prediction Model for the General Population
Authors: Spaeth Erika L. , Dite Gillian S. , Hopper John L. , Allman Richard
Published: May 2023

Supplementary Table S4 shows the expected and observed 5-year risks for each model by decile of risk
Supplementary Table S3 from Validation of an Abridged Breast Cancer Risk Prediction Model for the General Population
Authors: Spaeth Erika L. , Dite Gillian S. , Hopper John L. , Allman Richard
Published: May 2023

Supplementary Table S3 shows the characteristics of affected and unaffected participants
Supplementary Table S1 from Validation of an Abridged Breast Cancer Risk Prediction Model for the General Population
Authors: Spaeth Erika L. , Dite Gillian S. , Hopper John L. , Allman Richard
Published: May 2023

Supplementary Table S1 shows the relative risks assigned for first-degree family history of breast cancer
Supplemental Table 2 from Stressful Life Events, Social Support, and Incident Breast Cancer by Estrogen Receptor Status
Authors: Lawrence Wayne R. , McDonald Jasmine A. , Williams Faustine , Shiels Meredith S. , Freedman Neal D. , Lin Ziqiang , Magnani Jared W.
Published: May 2023

Supplemental Table 2: Presents the hazard ratios for the association between Stressful Life Events and incident breast cancer by participant characteristics and estrogen receptor status.
Supplementary Table S3 from Simple Prediction Model for Colorectal Serrated Polyps: Development and External Validation Study in U.S. Prospective Cohorts
Authors: Lyu Zhangyan , Hang Dong , He Xiaosheng , Wu Kana , Cao Yin , Rosner Bernard , Chan Andrew T. , Ogino Shuji , Li Ni , Dai Min , Giovannucci Edward L. , Song Mingyang
Published: May 2023

Supplementary Table S3: Associations of the included predictors with the risk of high-risk SPs in the NHS and NHS2.
Supplementary Table S2 from Simple Prediction Model for Colorectal Serrated Polyps: Development and External Validation Study in U.S. Prospective Cohorts
Authors: Lyu Zhangyan , Hang Dong , He Xiaosheng , Wu Kana , Cao Yin , Rosner Bernard , Chan Andrew T. , Ogino Shuji , Li Ni , Dai Min , Giovannucci Edward L. , Song Mingyang
Published: May 2023

Supplementary Table S2: Associations of the included predictors with the risk of high-risk SPs by sex.
Supplementary Table S1 from Simple Prediction Model for Colorectal Serrated Polyps: Development and External Validation Study in U.S. Prospective Cohorts
Authors: Lyu Zhangyan , Hang Dong , He Xiaosheng , Wu Kana , Cao Yin , Rosner Bernard , Chan Andrew T. , Ogino Shuji , Li Ni , Dai Min , Giovannucci Edward L. , Song Mingyang
Published: May 2023

Supplementary Table S1: Characteristics of study participants in the NHS and NHS2 by high-risk SPs.
Supplementary Table S2 from Precision Cut Lung Slices as a Preclinical Model for Non–Small Cell Lung Cancer Chemoprevention
Authors: Sompel Kayla , Smith Alex J. , Hauer Caroline , Elango Alamelu P. , Clamby Eric T. , Keith Robert L. , Tennis Meredith A.
Published: May 2023

Supplementary Table S2 lists antibody information for immunofluorescence in Figure 5.
Supplementary Table S1 from Precision Cut Lung Slices as a Preclinical Model for Non–Small Cell Lung Cancer Chemoprevention
Authors: Sompel Kayla , Smith Alex J. , Hauer Caroline , Elango Alamelu P. , Clamby Eric T. , Keith Robert L. , Tennis Meredith A.
Published: May 2023

Supplementary Table S1 lists targets in the dot blots for Figures 3D and 4C.
Supplementary Figure S2 from Simple Prediction Model for Colorectal Serrated Polyps: Development and External Validation Study in U.S. Prospective Cohorts
Authors: Lyu Zhangyan , Hang Dong , He Xiaosheng , Wu Kana , Cao Yin , Rosner Bernard , Chan Andrew T. , Ogino Shuji , Li Ni , Dai Min , Giovannucci Edward L. , Song Mingyang
Published: May 2023

Supplementary Figure S2: The calibration plot of the simple risk prediction model for high-risk serrated polyps (SPs) across deciles of predicted risk, in women and men.
Supplementary Figure S5 from Precision Cut Lung Slices as a Preclinical Model for Non–Small Cell Lung Cancer Chemoprevention
Authors: Sompel Kayla , Smith Alex J. , Hauer Caroline , Elango Alamelu P. , Clamby Eric T. , Keith Robert L. , Tennis Meredith A.
Published: May 2023

Supplementary Figure S5 shows a representative immunofluorescence image for Figure 5.
Supplementary Figure S1 from Simple Prediction Model for Colorectal Serrated Polyps: Development and External Validation Study in U.S. Prospective Cohorts
Authors: Lyu Zhangyan , Hang Dong , He Xiaosheng , Wu Kana , Cao Yin , Rosner Bernard , Chan Andrew T. , Ogino Shuji , Li Ni , Dai Min , Giovannucci Edward L. , Song Mingyang
Published: May 2023

Supplementary Figure S1: The flowchart for inclusion and exclusion of study participants in the NHS, NHS2, and HPFS.
Supplementary Figure S3 from Precision Cut Lung Slices as a Preclinical Model for Non–Small Cell Lung Cancer Chemoprevention
Authors: Sompel Kayla , Smith Alex J. , Hauer Caroline , Elango Alamelu P. , Clamby Eric T. , Keith Robert L. , Tennis Meredith A.
Published: May 2023

Supplementary Figure S3 shows a representative immunofluorescence image for Figure 5.
Supplementary Figure S1 from Precision Cut Lung Slices as a Preclinical Model for Non–Small Cell Lung Cancer Chemoprevention
Authors: Sompel Kayla , Smith Alex J. , Hauer Caroline , Elango Alamelu P. , Clamby Eric T. , Keith Robert L. , Tennis Meredith A.
Published: May 2023

Supplementary Figure S1 shows a dot blot for Figure 3D.
Data from Simple Prediction Model for Colorectal Serrated Polyps: Development and External Validation Study in U.S. Prospective Cohorts
Authors: Lyu Zhangyan , Hang Dong , He Xiaosheng , Wu Kana , Cao Yin , Rosner Bernard , Chan Andrew T. , Ogino Shuji , Li Ni , Dai Min , Giovannucci Edward L. , Song Mingyang
Published: May 2023

Abstract
Serrated polyps (SP) are precursors for colorectal cancer and contribute disproportionately to postcolonoscopy cancers. Leveraging three U.S. cohorts (43,974 women and 5,322 men), we developed prediction models for high-risk SPs (sized ≥10 mm or ≥3) among individuals undergoing their first colonoscopy screening. We then validated the model in the Partners Colonoscopy Cohort (51,203 women and 39,077 men). We evaluated discrimination and calibration using the C-statistic and Hosmer–Lemeshow test, respectively. The age and family history model generated a C-statistic [95% confidence interval (CI)] of 0.57 (0.56–0.58) in women and 0.58 (0.55–0.61) in men. Further inclusion of smoking, alcohol, and body mass index (the simple model) increased the C-statistic (95% CI) to 0.68 (0.67–0.69) in women and 0.68 (0.66–0.71) in men (all P < 0.001). Adding more predictors did not provide much incremental predictivity. In the validation cohort, moderate discrimination was observed in both women (0.60, 0.58–0.61) and men (0.60, 0.59–0.62). Notably, the simple model also yielded similar C-statistics for a composite endpoint of SPs and high-risk conventional adenomas (women, 0.62, 0.62–0.63; men, 0.63, 0.61–0.64). The model was adequately calibrated in both sets of cohorts. In summary, we developed and externally validated a simple prediction model based on five major risk factors for high-risk SPs that may be useful for healthy lifestyle recommendations and tailored colorectal cancer screening.
Prevention Relevance:
On the basis of four prospective studies in the United States, we developed and externally validated a simple risk prediction model for high-risk SPs in the setting of colonoscopy screening. Our model showed moderate discriminatory accuracy and has potential utility for individualized risk assessment, healthy lifestyle recommendations, and tailored colorectal cancer prevention.
Data from Precision Cut Lung Slices as a Preclinical Model for Non–Small Cell Lung Cancer Chemoprevention
Authors: Sompel Kayla , Smith Alex J. , Hauer Caroline , Elango Alamelu P. , Clamby Eric T. , Keith Robert L. , Tennis Meredith A.
Published: May 2023

Abstract
Lung cancer chemoprevention is critical to addressing cancer burden in high-risk populations. Chemoprevention clinical trials rely on data from preclinical models; however, in vivo studies have high financial, technical, and staffing requirements. Precision cut lung slices (PCLS) provide an ex vivo model that maintains the structure and function of native tissues. This model can be used for mechanistic investigations and drug screenings and reduces the number of animals and time required to test hypotheses compared with in vivo studies. We tested the use of PCLS for chemoprevention studies, demonstrating recapitulation of in vivo models. Treatment of PCLS with the PPARγ agonizing chemoprevention agent iloprost produced similar effects on gene expression and downstream signaling as in vivo models. This occurred in both wild-type tissue and Frizzled 9 knockout tissue, a transmembrane receptor required for iloprost's preventive activity. We explored new areas of iloprost mechanisms by measuring immune and inflammation markers in PCLS tissue and media, and immune cell presence with immunofluorescence. To demonstrate the potential for drug screening, we treated PCLS with additional lung cancer chemoprevention agents and confirmed activity markers in culture. PCLS offers an intermediate step for chemoprevention research between in vitro and in vivo models that can facilitate drug screening prior to in vivo studies and support mechanistic studies with more relevant tissue environments and functions than in vitro models.
Prevention Relevance:
PCLS could be a new model for premalignancy and chemoprevention research, and this work evaluates the model with tissue from prevention-relevant genetic and carcinogen exposed in vivo mouse models, in addition to evaluating chemoprevention agents.
Supplementary Table S8 from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers
Authors: Gunn Kathryn , Myllykoski Matti , Cao John Z. , Ahmed Manna , Huang Bofu , Rouaisnel Betty , Diplas Bill H. , Levitt Michael M. , Looper Ryan , Doench John G. , Ligon Keith L. , Kornblum Harley I. , McBrayer Samuel K. , Yan Hai , Duy Cihangir , Godley Lucy A. , Koivunen Peppi , Losman Julie-Aurore
Published: May 2023

Supplementary Table S8 shows the pathway analysis of the expression data from Supplementary Table S7.
Supplementary Table S7 from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers
Authors: Gunn Kathryn , Myllykoski Matti , Cao John Z. , Ahmed Manna , Huang Bofu , Rouaisnel Betty , Diplas Bill H. , Levitt Michael M. , Looper Ryan , Doench John G. , Ligon Keith L. , Kornblum Harley I. , McBrayer Samuel K. , Yan Hai , Duy Cihangir , Godley Lucy A. , Koivunen Peppi , Losman Julie-Aurore
Published: May 2023

Supplementary Table S7 shows the gene set enrichment analysis gene set that corresponds to Figure 4E.
Supplementary Table S5 from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers
Authors: Gunn Kathryn , Myllykoski Matti , Cao John Z. , Ahmed Manna , Huang Bofu , Rouaisnel Betty , Diplas Bill H. , Levitt Michael M. , Looper Ryan , Doench John G. , Ligon Keith L. , Kornblum Harley I. , McBrayer Samuel K. , Yan Hai , Duy Cihangir , Godley Lucy A. , Koivunen Peppi , Losman Julie-Aurore
Published: May 2023

Supplementary Table S5 shows the rank order list of genes targeted by sgRNAs enriched in the custom minipool CRISPR/Cas9 knockout screens.
Supplementary Table S11 from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers
Authors: Gunn Kathryn , Myllykoski Matti , Cao John Z. , Ahmed Manna , Huang Bofu , Rouaisnel Betty , Diplas Bill H. , Levitt Michael M. , Looper Ryan , Doench John G. , Ligon Keith L. , Kornblum Harley I. , McBrayer Samuel K. , Yan Hai , Duy Cihangir , Godley Lucy A. , Koivunen Peppi , Losman Julie-Aurore
Published: May 2023

Supplementary Table S11 shows the characteristics of the primary glioma patient samples.
Supplementary Table S10 from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers
Authors: Gunn Kathryn , Myllykoski Matti , Cao John Z. , Ahmed Manna , Huang Bofu , Rouaisnel Betty , Diplas Bill H. , Levitt Michael M. , Looper Ryan , Doench John G. , Ligon Keith L. , Kornblum Harley I. , McBrayer Samuel K. , Yan Hai , Duy Cihangir , Godley Lucy A. , Koivunen Peppi , Losman Julie-Aurore
Published: May 2023

Supplementary Table S10 shows the gene set enrichment analysis gene set that corresponds to Figure S6B.
Supplementary Figure S8 from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers
Authors: Gunn Kathryn , Myllykoski Matti , Cao John Z. , Ahmed Manna , Huang Bofu , Rouaisnel Betty , Diplas Bill H. , Levitt Michael M. , Looper Ryan , Doench John G. , Ligon Keith L. , Kornblum Harley I. , McBrayer Samuel K. , Yan Hai , Duy Cihangir , Godley Lucy A. , Koivunen Peppi , Losman Julie-Aurore
Published: May 2023

Characterization of isogenic IHA cell lines.
Supplementary Figure S7 from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers
Authors: Gunn Kathryn , Myllykoski Matti , Cao John Z. , Ahmed Manna , Huang Bofu , Rouaisnel Betty , Diplas Bill H. , Levitt Michael M. , Looper Ryan , Doench John G. , Ligon Keith L. , Kornblum Harley I. , McBrayer Samuel K. , Yan Hai , Duy Cihangir , Godley Lucy A. , Koivunen Peppi , Losman Julie-Aurore
Published: May 2023

5mC levels in primary AML and primary glioma samples and in MCTS lines.
Supplementary Figure S5 from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers
Authors: Gunn Kathryn , Myllykoski Matti , Cao John Z. , Ahmed Manna , Huang Bofu , Rouaisnel Betty , Diplas Bill H. , Levitt Michael M. , Looper Ryan , Doench John G. , Ligon Keith L. , Kornblum Harley I. , McBrayer Samuel K. , Yan Hai , Duy Cihangir , Godley Lucy A. , Koivunen Peppi , Losman Julie-Aurore
Published: May 2023

Characterization of KDM5A mutants.
Supplementary Figure S3 from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers
Authors: Gunn Kathryn , Myllykoski Matti , Cao John Z. , Ahmed Manna , Huang Bofu , Rouaisnel Betty , Diplas Bill H. , Levitt Michael M. , Looper Ryan , Doench John G. , Ligon Keith L. , Kornblum Harley I. , McBrayer Samuel K. , Yan Hai , Duy Cihangir , Godley Lucy A. , Koivunen Peppi , Losman Julie-Aurore
Published: May 2023

Trimethyl-H3K4 is not enriched upon knock-down of TET2 in TF-1 cells.
Supplementary Figure S1 from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers
Authors: Gunn Kathryn , Myllykoski Matti , Cao John Z. , Ahmed Manna , Huang Bofu , Rouaisnel Betty , Diplas Bill H. , Levitt Michael M. , Looper Ryan , Doench John G. , Ligon Keith L. , Kornblum Harley I. , McBrayer Samuel K. , Yan Hai , Duy Cihangir , Godley Lucy A. , Koivunen Peppi , Losman Julie-Aurore
Published: May 2023

Characterization of isogenic TF-1 cell lines expressing TET2-targeting shRNAs.
Data from (R)-2-hydroxyglutarate inhibits KDM5 histone lysine demethylases to drive transformation in IDH-mutant cancers
Authors: Gunn Kathryn , Myllykoski Matti , Cao John Z. , Ahmed Manna , Huang Bofu , Rouaisnel Betty , Diplas Bill H. , Levitt Michael M. , Looper Ryan , Doench John G. , Ligon Keith L. , Kornblum Harley I. , McBrayer Samuel K. , Yan Hai , Duy Cihangir , Godley Lucy A. , Koivunen Peppi , Losman Julie-Aurore
Published: May 2023

Abstract
Oncogenic mutations in isocitrate dehydrogenase (IDH)-1 and -2 occur in a wide range of cancers, including acute myeloid leukemia (AML) and glioma. Mutant IDH enzymes convert 2-oxoglutarate (2OG) to (R)-2-hydroxyglutarate ((R)-2HG)), an oncometabolite that is hypothesized to promote cellular transformation by dysregulating 2OG-dependent enzymes. The only (R)-2HG target that has been convincingly shown to contribute to transformation by mutant IDH is the myeloid tumor suppressor TET2. However, there is ample evidence to suggest that (R)-2HG has other functionally relevant targets in IDH-mutant cancers. Here, we show that (R)-2HG inhibits KDM5 histone lysine demethylases and that this inhibition contributes to cellular transformation in IDH-mutant AML and IDH-mutant glioma. These studies provide the first evidence of a functional link between dysregulation of histone lysine methylation and transformation in IDH-mutant cancers.
Supplementary Tables S1-5 from METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL
Authors: Wu Yiming , Jin Meiling , Fernandez Mike , Hart Kevyn L. , Liao Aijun , Ge Xinzhou , Fernandes Stacey M. , McDonald Tinisha , Chen Zhenhua , Röth Daniel , Ghoda Lucy Y. , Marcucci Guido , Kalkum Markus , Pillai Raju K. , Danilov Alexey V. , Li Jingyi Jessica , Chen Jianjun , Brown Jennifer R. , Rosen Steven T. , Siddiqi Tanya , Wang Lili
Published: May 2023

Table S1 shows CLL sample information; Table S2 shows protein expression detected in CLL and normal B cells using TMT proteomics; Table S3 shows top 150 transcripts with highest m6A density in B cells; Table S4 shows sequences of shRNAs, sgRNAs, and primers used in our study; Table S5 shows cellular pathways enriched in our study.
Supplementary Figures S1-8 from METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL
Authors: Wu Yiming , Jin Meiling , Fernandez Mike , Hart Kevyn L. , Liao Aijun , Ge Xinzhou , Fernandes Stacey M. , McDonald Tinisha , Chen Zhenhua , Röth Daniel , Ghoda Lucy Y. , Marcucci Guido , Kalkum Markus , Pillai Raju K. , Danilov Alexey V. , Li Jingyi Jessica , Chen Jianjun , Brown Jennifer R. , Rosen Steven T. , Siddiqi Tanya , Wang Lili
Published: May 2023

Fig S1. SF3B1 mutant CLL samples had pervasive changes in 3’ splice site.
Fig S2. Omics analyses identify widespread post-transcriptional upregulation of splicing factors in CLL.
Fig S3. Abundance of spliceosome complexes and RNA-binding proteins are associated with clinical outcomes in CLL.
Fig S4. METTL3 is consistently upregulated along with differential m6A modification on transcripts of RNA splicing process in CLL.
Fig S5. KO or pharmacological inhibition of METTL3 impacts cell growth.
Fig S6. KO or pharmacological inhibition of METTL3 impacts apoptosis, cell cycle, and splicing factor abundance.
Fig S7. Splicing factors are either direct or indirect targets of METTL3.
Fig S8. Validation of association between m6A and splicing factor abundance using dCasRx-METTL3.
Supplementary Tables from Molecular Evolution of Classic Hodgkin Lymphoma Revealed Through Whole-Genome Sequencing of Hodgkin and Reed Sternberg Cells
Authors: Maura Francesco , Ziccheddu Bachisio , Xiang Jenny Z. , Bhinder Bhavneet , Rosiene Joel , Abascal Federico , Maclachlan Kylee H. , Eng Kenneth Wha , Uppal Manik , He Feng , Zhang Wei , Gao Qi , Yellapantula Venkata D. , Trujillo-Alonso Vicenta , Park Sunita I. , Oberley Matthew J. , Ruckdeschel Elizabeth , Lim Megan S. , Wertheim Gerald B. , Barth Matthew J. , Horton Terzah M. , Derkach Andriy , Kovach Alexandra E. , Forlenza Christopher J. , Zhang Yanming , Landgren Ola , Moskowitz Craig H. , Cesarman Ethel , Imielinski Marcin , Elemento Olivier , Roshal Mikhail , Giulino-Roth Lisa
Published: May 2023

Supplementary Tables S1-S20
Supplementary Figures from Molecular Evolution of Classic Hodgkin Lymphoma Revealed Through Whole-Genome Sequencing of Hodgkin and Reed Sternberg Cells
Authors: Maura Francesco , Ziccheddu Bachisio , Xiang Jenny Z. , Bhinder Bhavneet , Rosiene Joel , Abascal Federico , Maclachlan Kylee H. , Eng Kenneth Wha , Uppal Manik , He Feng , Zhang Wei , Gao Qi , Yellapantula Venkata D. , Trujillo-Alonso Vicenta , Park Sunita I. , Oberley Matthew J. , Ruckdeschel Elizabeth , Lim Megan S. , Wertheim Gerald B. , Barth Matthew J. , Horton Terzah M. , Derkach Andriy , Kovach Alexandra E. , Forlenza Christopher J. , Zhang Yanming , Landgren Ola , Moskowitz Craig H. , Cesarman Ethel , Imielinski Marcin , Elemento Olivier , Roshal Mikhail , Giulino-Roth Lisa
Published: May 2023

All supplementary figures S1-S17
Supplementary Data 2 from Molecular Evolution of Classic Hodgkin Lymphoma Revealed Through Whole-Genome Sequencing of Hodgkin and Reed Sternberg Cells
Authors: Maura Francesco , Ziccheddu Bachisio , Xiang Jenny Z. , Bhinder Bhavneet , Rosiene Joel , Abascal Federico , Maclachlan Kylee H. , Eng Kenneth Wha , Uppal Manik , He Feng , Zhang Wei , Gao Qi , Yellapantula Venkata D. , Trujillo-Alonso Vicenta , Park Sunita I. , Oberley Matthew J. , Ruckdeschel Elizabeth , Lim Megan S. , Wertheim Gerald B. , Barth Matthew J. , Horton Terzah M. , Derkach Andriy , Kovach Alexandra E. , Forlenza Christopher J. , Zhang Yanming , Landgren Ola , Moskowitz Craig H. , Cesarman Ethel , Imielinski Marcin , Elemento Olivier , Roshal Mikhail , Giulino-Roth Lisa
Published: May 2023

R code of our analysis clock like mutational signatures in Hodgkin lymphoma WGS and WES.
Supplementary Table S8 from In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Authors: Vujovic Ana , de Rooij Laura , Chahi Ava Keyvani , Chen He Tian , Yee Brian A. , Loganathan Sampath K. , Liu Lina , Chan Derek C.H. , Tajik Amanda , Tsao Emily , Moreira Steven , Joshi Pratik , Xu Joshua , Wong Nicholas , Balde Zaldy , Jahangiri Soheil , Zandi Sasan , Aigner Stefan , Dick John E. , Minden Mark D. , Schramek Daniel , Yeo Gene W. , Hope Kristin J.
Published: May 2023

Table S8 shows transcripts from the ELAVL1 knockout RNA-sequencing data set that are (a) alternatively spliced and (b) alternatively spliced as well as bound by ELAVL1 as identified by eCLIP-sequencing.
Supplementary Table S7 from In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Authors: Vujovic Ana , de Rooij Laura , Chahi Ava Keyvani , Chen He Tian , Yee Brian A. , Loganathan Sampath K. , Liu Lina , Chan Derek C.H. , Tajik Amanda , Tsao Emily , Moreira Steven , Joshi Pratik , Xu Joshua , Wong Nicholas , Balde Zaldy , Jahangiri Soheil , Zandi Sasan , Aigner Stefan , Dick John E. , Minden Mark D. , Schramek Daniel , Yeo Gene W. , Hope Kristin J.
Published: May 2023

Table S7 shows (a) reproducible peaks and (b) GO analysis of ELAVL1-bound transcripts identified in the eCLIP-sequencing data set. The negatively enriched (c) and positively-enriched (d) gene sets identified by GSEA of ELAVL1-bound and differentially expressed transcripts from the RN2c RNA-sequencing data set are shown.
Supplementary Table S6 from In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Authors: Vujovic Ana , de Rooij Laura , Chahi Ava Keyvani , Chen He Tian , Yee Brian A. , Loganathan Sampath K. , Liu Lina , Chan Derek C.H. , Tajik Amanda , Tsao Emily , Moreira Steven , Joshi Pratik , Xu Joshua , Wong Nicholas , Balde Zaldy , Jahangiri Soheil , Zandi Sasan , Aigner Stefan , Dick John E. , Minden Mark D. , Schramek Daniel , Yeo Gene W. , Hope Kristin J.
Published: May 2023

Table S6 shows altered gene sets identified by GSEA of the ELAVL1 knockout RN2c RNA-sequencing data set.
Supplementary Table S5 from In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Authors: Vujovic Ana , de Rooij Laura , Chahi Ava Keyvani , Chen He Tian , Yee Brian A. , Loganathan Sampath K. , Liu Lina , Chan Derek C.H. , Tajik Amanda , Tsao Emily , Moreira Steven , Joshi Pratik , Xu Joshua , Wong Nicholas , Balde Zaldy , Jahangiri Soheil , Zandi Sasan , Aigner Stefan , Dick John E. , Minden Mark D. , Schramek Daniel , Yeo Gene W. , Hope Kristin J.
Published: May 2023

Table S5 shows the log2 fold change of differentially expressed transcripts from the ELAVL1 knockout RN2c RNA-sequencing data set.
Supplementary Table S4 from In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Authors: Vujovic Ana , de Rooij Laura , Chahi Ava Keyvani , Chen He Tian , Yee Brian A. , Loganathan Sampath K. , Liu Lina , Chan Derek C.H. , Tajik Amanda , Tsao Emily , Moreira Steven , Joshi Pratik , Xu Joshua , Wong Nicholas , Balde Zaldy , Jahangiri Soheil , Zandi Sasan , Aigner Stefan , Dick John E. , Minden Mark D. , Schramek Daniel , Yeo Gene W. , Hope Kristin J.
Published: May 2023

Table S4 shows limiting dilution analysis of secondary recipients transplanted with DMSO- or MS-444-treated bone marrow from primary mice
Supplementary Table S2 from In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Authors: Vujovic Ana , de Rooij Laura , Chahi Ava Keyvani , Chen He Tian , Yee Brian A. , Loganathan Sampath K. , Liu Lina , Chan Derek C.H. , Tajik Amanda , Tsao Emily , Moreira Steven , Joshi Pratik , Xu Joshua , Wong Nicholas , Balde Zaldy , Jahangiri Soheil , Zandi Sasan , Aigner Stefan , Dick John E. , Minden Mark D. , Schramek Daniel , Yeo Gene W. , Hope Kristin J.
Published: May 2023

Table S2 shows sequences of (a) sgRNAs from the RBP screen, (b) sequencing primers, (c) shRNAs and human-targeting sgRNAs, (d) eCLIP oligos.
Supplementary Table S1 from In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Authors: Vujovic Ana , de Rooij Laura , Chahi Ava Keyvani , Chen He Tian , Yee Brian A. , Loganathan Sampath K. , Liu Lina , Chan Derek C.H. , Tajik Amanda , Tsao Emily , Moreira Steven , Joshi Pratik , Xu Joshua , Wong Nicholas , Balde Zaldy , Jahangiri Soheil , Zandi Sasan , Aigner Stefan , Dick John E. , Minden Mark D. , Schramek Daniel , Yeo Gene W. , Hope Kristin J.
Published: May 2023

Table S1 shows expression of RBPs in an RNA-sequencing data set of human bone marrow hematopoietic stem and progenitor subpopulations.
Supplementary Figure S5 from In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Authors: Vujovic Ana , de Rooij Laura , Chahi Ava Keyvani , Chen He Tian , Yee Brian A. , Loganathan Sampath K. , Liu Lina , Chan Derek C.H. , Tajik Amanda , Tsao Emily , Moreira Steven , Joshi Pratik , Xu Joshua , Wong Nicholas , Balde Zaldy , Jahangiri Soheil , Zandi Sasan , Aigner Stefan , Dick John E. , Minden Mark D. , Schramek Daniel , Yeo Gene W. , Hope Kristin J.
Published: May 2023

Supplemental Figure S5 shows the effects of DHTS treatment on THP-1 and human primary AML cells in vitro, the effects of MS-444 treatment on human umbilical cord blood in vivo, and validation of ELAVL1 overexpression by western blot.
Supplementary Figure S4 from In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Authors: Vujovic Ana , de Rooij Laura , Chahi Ava Keyvani , Chen He Tian , Yee Brian A. , Loganathan Sampath K. , Liu Lina , Chan Derek C.H. , Tajik Amanda , Tsao Emily , Moreira Steven , Joshi Pratik , Xu Joshua , Wong Nicholas , Balde Zaldy , Jahangiri Soheil , Zandi Sasan , Aigner Stefan , Dick John E. , Minden Mark D. , Schramek Daniel , Yeo Gene W. , Hope Kristin J.
Published: May 2023

Supplemental Figure S4 shows the validation of ELAVL1 knockdown by western blot and effects of ELAVL1 loss on human primary AML cells in vitro and in vivo.
Supplementary Figure S2 from In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Authors: Vujovic Ana , de Rooij Laura , Chahi Ava Keyvani , Chen He Tian , Yee Brian A. , Loganathan Sampath K. , Liu Lina , Chan Derek C.H. , Tajik Amanda , Tsao Emily , Moreira Steven , Joshi Pratik , Xu Joshua , Wong Nicholas , Balde Zaldy , Jahangiri Soheil , Zandi Sasan , Aigner Stefan , Dick John E. , Minden Mark D. , Schramek Daniel , Yeo Gene W. , Hope Kristin J.
Published: May 2023

Supplemental Figure S2 shows validation of sgRNA -mediated knockout of hit RBPs, comparison of hit RBP depletion in RN2c in vitro versus in vivo, effects of ELAVL1 loss on human AML cell lines, characteristics of the MLL-AF9 AML mouse model, and ELAVL1 expression in normal hematopoietic cells.
Supplementary Figure S1 from In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Authors: Vujovic Ana , de Rooij Laura , Chahi Ava Keyvani , Chen He Tian , Yee Brian A. , Loganathan Sampath K. , Liu Lina , Chan Derek C.H. , Tajik Amanda , Tsao Emily , Moreira Steven , Joshi Pratik , Xu Joshua , Wong Nicholas , Balde Zaldy , Jahangiri Soheil , Zandi Sasan , Aigner Stefan , Dick John E. , Minden Mark D. , Schramek Daniel , Yeo Gene W. , Hope Kristin J.
Published: May 2023

Supplemental Figure S1 shows expression of RBPs in healthy HSPCs and RN2c cells, sgRNA drop out dynamics in primary and secondary transplants, the molecular functions and biological processes associated with the hit RBPs and their gene essentialities.
Abstract A04: Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia
Authors: Wang Eric , Abdel-Wahab Omar , Bradley Robert K , Bello Jose Mario , Kim Won Jun , Bossard Carine
Published: May 2023

Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR/Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncovered a selective dependency on RNA splicing factors whose loss preferentially enhanced response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augmented response to venetoclax in leukemia yet was completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition led to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. A novel inhibitor of splicing kinase families CLKs and DYRKs led to aberrant splicing of key splicing and apoptotic factors that synergized with venetoclax and overcame resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments.

Citation Format: Eric Wang, Omar Abdel-Wahab, Robert K Bradley, Jose Mario Bello, Won Jun Kim, Carine Bossard. Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A04.