64th ASH Annual Meeting and Exposition: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Molecular Consequences of MPN Driver and Co-mutations

Symposia: Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational Oral and Poster Abstracts
Oral

Research, Fundamental Science, Bleeding and Clotting, MDS, adult, Translational Research, MPN, Non-Biological therapies, CML, genomics, bioinformatics, Chemotherapy, platelet disorders, Chronic Myeloid Malignancies, hematopoiesis, pediatric, Diseases, immune mechanism, Therapies, immunology, thrombotic disorders, metabolism, computational biology, young adult , Myeloid Malignancies, Biological Processes, emerging technologies, Pharmacology, molecular biology, Technology and Procedures, gene editing, Human, Study Population, profiling, pathogenesis, imaging, Animal model, machine learning, molecular testing, omics technologies, Pathology

275-277 (Ernest N. Morial Convention Center)

Moderators:

Bridget K Marcellino, MD, PhD, Icahn School of Medicine at Mount Sinai and Rebekka K. Schneider, MD, PhD, Erasmus MC

Disclosures:

No relevant conflicts of interest to declare.

In this session, so far unappreciated molecular and phenotypic consequences of MPN driver and co-mutations will be discussed, using murine models and primary patient samples. Transcriptional and metabolic profiling of MPN initiating cells, platelets as well as the bone marrow microenvironment reveal novel mechanisms that drive inflammation and remodelling of the hematopoietic stem cell niche in MPN, and abnormalities in platelet function. The differential effect of type I and type II CALR mutations on the protein structure and chaperone function will be discussed, as well as germline determinants of variation in platelet counts and generation of a new genetically engineered mouse model of histiocytic neoplasms.

9:30 AM

451

Type 2 but Not Type 1 Calreticulin Mutants Exhibit Loss of Chaperone Function Due to C-Terminal Structural Interference, and Bind to Wild Type Calreticulin in a Dominant Negative Manner

Nicole S Arellano, BA^1,2, Jacqueline Gomez²^*, Michele Ciboddo, MD²^*, Hunter Blaylock²^*, Deborah Rodriguez, BA^1,2^*, Amy K Chen²^*, Melissa Gaviria²^*, Lulu Allie²^*, Alex Rosencrance^2,3^*, Harrison S Greenbaum²^*, Elisa Rumi⁴^*, Oscar Borsani, MD⁴, Ilaria Carola Casetti, MD, PhD⁴^*, Daniela Pietra, PhD⁴^*, Silvia Catricalá⁴^* and Shannon Elf, PhD^1,2

¹University of Chicago, The Committee on Cancer Biology, Chicago, IL
²University of Chicago, The Ben May Department for Cancer Research, Chicago, IL
³University of Chicago, Pritzker School of Medicine, Chicago, IL
⁴Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

9:45 AM

452

Mutant Srsf2 Diminishes Jak2^V617F-Induced Erythrocytosis in Mice and Is Associated with Lower Hemoglobin in Patients with Chronic Phase JAK2-Mutant MPN

Anna E Marneth, PhD¹, Jonas S. Jutzi, MD, PhD¹, Chulwoo J. Kim, BA¹^*, Charles Laurore, BA¹^*, Anastasia Tishena, BA¹^*, Frederike Kramer, PhD¹, Azucena V. Rocha, BA¹^*, Mohammed Wazir, MD²^*, Lachelle D. Weeks, MD, PhD^3,4, Joan How, MD^1,4,5, Maximilian F. Stahl, MD⁶, Marlise R. Luskin, MD⁴, R. Coleman Lindsley, MD, PhD⁴^*, Olga Pozdnyakova, MD, PhD⁷^*, Timothy A. Graubert, MD⁸ and Ann Mullally, MD^1,4,9

¹Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
²Division of General Internal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
³Center for Prevention of Progression, Dana-Farber Cancer Institute, Boston, MA
⁴Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
⁵Department of Medical Oncology, Massachusetts General Hospital, Boston
⁶Department of Medical Oncology, Dana-Farber Institute, Boston, MA
⁷Department of Pathology, Brigham and Women's Hospital, Boston, MA
⁸Massachusetts General Hospital Cancer Center, Charlestown, MA
⁹Broad Institute, Cambridge, MA

10:00 AM

453

Cross-Talk between Hematopoietic Cells and Fibroblast Subsets Drives Inflammation and Remodelling of the Bone Marrow Microenvironment in Myeloproliferative Neoplasms

Rong Li, PhD^1,2,3^*, Michela Colombo, PhD^1,3^*, Guanlin Wang, PhD^1,3,4,5,6^*, Sally-Ann Clark, PhD¹^*, Antonio Rodriguez-Romera¹^*, Yiran Meng, PhD¹^*, Abdullah Khan, PhD¹, Wei Xiong Wen^1,6^*, Nikolaos Sousos, MD, MSc¹^*, Lauren Murphy¹^*, Christina Simoglou Karali, PhD¹^*, Korsuk Sirinukunwattana⁷^*, Jennifer O’Sullivan, MD¹^*, Ruggiero Norfo, PhD¹^*, Qian Cheng, PhD¹^*, Charlotte Brierley, MD, MRCP¹^*, Joana Carrelha, PhD¹^*, Zemin Ren, PhD¹^*, Gabriel A. Rabinovich⁸^*, Vijay A Rathinam, PhD⁹^*, Supat Thongjuea, PhD⁶^*, Daniel Royston, MD PhD¹⁰^*, Adam J Mead, MD PhD^1,10,11 and Bethan Psaila, MD, PhD^1,11,12

¹Medical Research Council Weatherall Institute of Molecular Medicine and NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
²Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, United Kingdom
³Co-first author, ., United Kingdom
⁴Shanghai Qi Zhi Institute, Shanghai, China
⁵Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
⁶MRC WIMM Centre for Computational Biology, University of Oxford, Oxford, United Kingdom
⁷Oxford Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, United Kingdom
⁸Laboratory of Glycomedicine, Institute of Biology and Experimental Medicine, National Research Council, Buenos Aires, Argentina; Faculty of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, ARG
⁹Department of Immunology, University of Connecticut Health School of Medicine, Farmington, CT
¹⁰Oxford University Hospitals NHS Trust, Oxford, United Kingdom
¹¹Co-senior author, ., United Kingdom
¹²MRC Weatherall Institute of Molecular Medicine, University of Oxford; Oxford University Hospitals NHS Trust, Oxford, United Kingdom

10:15 AM

454

Germline Missense Variants in SH2B3 Underpin Platelet Count Variation and Inherited MPN

Liesl Butler, MB BS^1,2^*, Christine Lee, BSc PhD³^*, Graham William Magor, BSc¹^*, Rhiannon Morris, BSc PhD⁴^*, Michael Tallack, MB BS PhD^5,6^*, Charlene Lam, BSc¹^*, Adam Ivey, BSc, MSc, PhD⁷^*, Jane Lin, BSc PhD⁸^*, Zihao Deng, BSc¹^*, Andrew Grigg, MBBS, MD, FRACP, FRCPA^9,10^*, Jane Mason, MBBS Hons, FRACP, FRCPA¹¹^*, Malaika Perchard, MB BS¹²^*, Helen Weston, MBBS, FRACP, FRCPA¹³^*, Nik Cummings, BSc^1,14^*, Andrew Brooks, BSc PhD¹⁵^*, Jeffrey J Babon, PhD¹⁶^*, Andrew J Murphy, BSc PhD¹⁷^*, Jessica M Salmon, BSc PhD¹^* and Andrew Charles Perkins, MBBS, PhD, FRACP, FRCPA^1,8,18,19

¹Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
²Department of Haematology, Alfred Hospital, Melbourne, VIC, Australia
³Diamantina Institute, The University of Queensland, Woolloongabba, AUS
⁴The Walter and Eliza Hall Institute of Medical Research, Melbourne University, Melbourne, VIC, Australia
⁵Mater Research Institute - University of Queensland, Brisbane, Australia
⁶Queensland Medical Laboratories, Brisbane, QLD, Australia
⁷Molecular Pathology, The Alfred Hospital, Melbourne, VIC, Australia
⁸Pathology, Alfred Hospital, Melbourne, VIC, Australia
⁹Department of Haematology, Austin Health, Melbourne, Australia
¹⁰Australasian Leukaemia and Lymphoma Group (ALLG), Melbourne, Australia
¹¹Queensland Haemophilia Centre, Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
¹²Royal Brisbane Women's and Children's Hospital, Brisbane, QLD, Australia
¹³Haematology Department, Sunshine Coast University Hospital, Sunshione Coast, QLD, Australia
¹⁴Pathology, Alfred Health, Melbourne, VIC, Australia
¹⁵The University of Queensland, Brisbane, AUS
¹⁶The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
¹⁷Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Australia
¹⁸Department of Haematology, Alfred Hospital, Melbourne, Australia
¹⁹Australasian Leukaemia and Lymphoma Group (ALLG), Richmond, VIC, Australia

10:30 AM

455

Transcriptional and Metabolic Profiling Reveals Alpha-Ketoglutarate As a Novel Mediator of Aberrant Platelet Activity and Inflammation in Myeloproliferative Neoplasms

Fan He, PhD¹, Angelo BA Laranjeira, PhD¹^*, Tim Kong, MS¹, Katrina Bark, MS²^*, Alice Liu, BS²^*, Maggie J. Allen, BS¹^*, Daniel AC Fisher, PhD¹^*, Mary Fulbright, MS¹^*, LaYow Yu¹^*, Nina M. Lasky, RVT, LAT²^*, Stephen M. Sykes, PhD³, Angelo D'Alessandro, PhD⁴, Jorge Di Paola, MD² and Stephen T Oh, MD, PhD⁵

¹Division of Hematology, Washington University School of Medicine in St. Louis, Saint Louis, MO
²Department of Pediatrics, Washington University School of Medicine in St. Louis, Saint Louis, MO
³Department of Pediatrics, Washington University, Saint Louis, MO
⁴Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO
⁵Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO

10:45 AM

456

RAF-Independent MEK Mutations Drive Histiocytic Neoplasms In Vivo and Are Sensitive to Single-Agent ERK Inhibition in Patients

Benjamin H Durham, MD^1,2, Michael E Singer, B.S.¹^*, Salima Benbarche, PhD¹, Caroline Erickson, B.S.¹^*, Jahan Rahman, PhD¹^*, David B. Solit, MD^1,3^*, Matthew Witkowski, PhD^4,5^*, Neal Rosen, MD, PhD¹^*, Omar Abdel-Wahab, MD^1,6,7 and Eli L Diamond, MD⁸^*

¹Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
²Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
³Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY
⁴Perlmutter Cancer Center at NYU Langone Health, New York University, New York, NY
⁵Pediatrics-Heme/Onc and Bone Marrow Transplantation, University of Colorado Anschutz, Aurora, CO
⁶Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
⁷Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
⁸Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY

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631.O2.6 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Molecular Consequences of MPN Driver and Co-mutations