Welcome to Dana-Farber's Research News
May 15, 2022
This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at: Michael_buller@dfci.harvard.edu.
Blood
Congenital Anemia Reveals Distinct Targeting Mechanisms for Master Transcription Factor GATA1
Ludwig LS, Lareau CA, Bao EL, Liu N, Myers SA, Verboon JM, Ulirsch JC, Luo W, Muus C, Fiorini C, Olive ME, Vockley CM, Munschauer M, Subramanian V, Chiarle R, Carr SA, Aryee MJ, Orkin SH, Regev A, Sankaran VG
Master regulators, such as the hematopoietic transcription factor (TF) GATA1, play an essential role in orchestrating lineage commitment and differentiation. However, the precise mechanisms by which such TFs regulate transcription through interactions with specific cis-regulatory elements remain incompletely understood. Here, we describe a form of congenital hemolytic anemia caused by missense mutations in an intrinsically disordered region of GATA1, with a poorly understood role in transcriptional regulation. Through integrative functional approaches, we demonstrate that these mutations perturb GATA1 transcriptional activity by partially impairing nuclear localization and selectively altering precise chromatin occupancy by GATA1. These alterations in chromatin occupancy and concordant chromatin accessibility changes alter faithful gene expression, with failure to both effectively silence and activate select genes necessary for effective terminal red cell production. We demonstrate how disease-causing mutations can reveal regulatory mechanisms that enable the faithful genomic targeting of master TFs during cellular differentiation.
Cell
Augmenting NK Cell-Based Immunotherapy by Targeting Mitochondrial Apoptosis
Pan R, Ryan J, Pan D, Wucherpfennig KW, Letai A
Interest in harnessing natural killer (NK) cells for cancer immunotherapy is rapidly growing. However, efficacy of NK cell-based immunotherapy remains limited in most trials. Strategies to augment the killing efficacy of NK cells are thus much needed. In the current study, we found that mitochondrial apoptosis (mtApoptosis) pathway is essential for efficient NK killing, especially at physiologically relevant effector-to-target ratios. Furthermore, NK cells can prime cancer cells for mtApoptosis and mitochondrial priming status affects cancer-cell susceptibility to NK-mediated killing. Interestingly, pre-activating NK cells confers on them resistance to BH3 mimetics. Combining BH3 mimetics with NK cells synergistically kills cancer cells in-vitro and suppresses tumor growth in vivo. The ideal BH3 mimetic to use in such an approach can be predicted by BH3 profiling. We herein report a rational and precision strategy to augment NK-based immunotherapy, which may be adaptable to T cell-based immunotherapies as well.
Journal of Clinical Oncology
Jacene H, Taplin ME, Sweeney C
Although most men with metastatic hormone-sensitive prostate cancer (mHSPC) die of prostate cancer (PCa), there remains significant outcome variability, with approximately 18.5% living 10 years or longer.1 Prognosis and management are determined in part by disease extent detected on conventional imaging (CIM; 99mTc Bone and computed tomography [CT] scan; Data Supplement, online only). With the advent of multiple new life-prolonging therapies, clinicians can better personalize therapy on the basis of these findings. However, the availability of new imaging modalities with varying performance characteristics has added more variables that affect clinical decision making.
Journal of Clinical Oncology
Sweeney CJ
We thank Marandino et al and agree that cognitive function is important and complex in men with metastatic, hormone-sensitive prostate cancer. Cognitive decline increases with age, as does the incidence of metastatic prostate cancer, and has been associated with a diagnosis of cancer, androgen deprivation therapy, early generation antiandrogens, novel androgen signaling inhibitors, and chemotherapy. ENZAMET provides unique information about self-ratings of cognitive function and other aspects of health-related quality of life (HRQoL) in men receiving these treatments for metastatic, hormone-sensitive prostate cancer.
Journal of Clinical Oncology
Therapy for Muscle-Invasive Urothelial Carcinoma: Controversies and Dilemmas
Sonpavde GP, Mouw KW, Mossanen M
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
Molecular Cell
Teh WP, Zhu H, Marto JA, Buhrlage SJ
Henning et al. (2022) report development of a novel class of agents, bivalent deubiquitinase (DUB)-targeting chimeras (DUBTACs), that can selectively stabilize protein targets. These findings encourage further pursuit of targeted protein stabilization as a new paradigm in chemical biology and drug discovery.
Nature
Breakage of Cytoplasmic Chromosomes by Pathological DNA Base Excision Repair
Tang S, Stokasimov E, Pellman D
Chromothripsis is a catastrophic mutational process that promotes tumorigenesis and causes congenital disease. Chromothripsis originates from aberrations of nuclei called micronuclei or chromosome bridge. These structures have fragile nuclear envelopes (NEs) that spontaneously rupture leading to DNA damage when chromatin is exposed to the interphase cytoplasm. Here, we identify a mechanism explaining a major fraction of this DNA damage. Micronuclei accumulate large amounts of RNA-DNA hybrids, which are edited by ADAR enzymes (adenine deaminases acting on RNA) to generate deoxyinosine (dI). dI is then converted into abasic sites by a DNA base excision repair (BER) glycosylase, MPG (N-methyl-purine DNA glycosylase). These abasic sites are cleaved by the BER endonuclease, APE1 (apurinic/apyrimidinic endonuclease), creating single-strand DNA nicks that can be converted to DNA double strand breaks by DNA replication or when closely spaced nicks occur on opposite strands. This model predicts that MPG should be able to remove the dI base from the DNA strand of RNA-DNA hybrids, which we demonstrate using pure proteins and oligonucleotide substrates. These findings identify a mechanism for fragmentation of micronuclear chromosomes, an important step in generating chromothripsis. Rather than breaking any normal chromosome, we propose that the eukaryotic cytoplasm only damages chromosomes with preexisting defects such as the DNA base abnormality described here.
Proceedings in the National Academy of Sciences of the U.S.A.
Wight AE, Sido JM, Degryse S, Ao L, Nakagawa H, Qiu Vivian Y, Shen X, Oseghali O, Kim HJ, Cantor H
Significance Regulatory T cells rely on active processes to maintain a suppressive phenotype inside a tumor, leading to increased tumor burden and worse cancer outcomes. Here, we report a pathway to interfere with regulatory T cell (Treg) stability by disrupting the expression of the interleukin 23 receptor. This approach increases Treg responsiveness to interleukin 12, leading to increased production of gamma-interferon and more efficient antitumor immune responses. The combined engagement of independent pathways to destabilize Treg through the interleukin 23 receptor and the glucocorticoid-induced TNFR-related protein receptor has a synergistic impact on the Treg phenotype and promotes antitumor immune responses. These findings expand our understanding of regulatory T-cell biology and offer tools for cancer immunotherapy.
Science
Burns KH
In 1988, physician-scientists studying the genetic basis of hemophilia discovered pathogenic long interspersed element 1 (LINE-1) insertions in the coagulation factor VIII gene. Therein was unequivocal evidence of a new mutagenic mechanism in humans: insertions of mobile genetic elements (transposons) originating from the mostly silent, repetitive sequences of the human genome. In subsequent years, insertional mutagenesis proved a recurrent, albeit uncommon, cause of genetic disease. Now, a paradigm shift is placing new emphasis on transposon control as a vital cellular function that is compromised by and potentially contributes to many diseases. Transposon expression and activity is perhaps most overt in cancers, although aberrant expression of LINE-1, endogenous retroviruses (ERVs), and other repeats have also been invoked as a dimension of developmental, degenerative, and autoimmune diseases. As rigorous and accessible tools are developed to investigate, new discoveries will clarify the roles of repetitive elements and their regulation in disease.
American Journal of Clinical Nutrition
Yuan C, Joh HK, Wang QL, Zhang Y, Smith-Warner SA, Wang M, Song M, Zhang X, Zoltick ES, Hur J, Chan AT, Meyerhardt JA, Ogino S, Ng K, Giovannucci EL, Wu K
American Journal of Hematology
Castillo JJ
Annals of Surgical Oncology
Minami CA, Jin G, Schonberg MA, Freedman RA, King TA, Mittendorf EA
Blood Advances
Whangbo J, Nikiforow S, Kim HT, Wahl J, Reynolds CG, Chamling Rai S, Kim S, Burden AT, Alyea EP, Cutler CS, Ho VT, Antin JH, Soiffer RJ, Ritz J, Koreth J
Blood Advances
Coping Strategies in Patients with Acute Myeloid Leukemia
Amonoo HL, Reynolds MJ, Nelson AM, Newcomb R, Johnson PC, Dhawale TM, Plotke R, Heuer L, Gillani S, Yang D, Deary EC, Daskalakis E, Goldschen L, Brunner A, Fathi AT, El-Jawahri A
Blood Advances
Gooptu M, Kim HT, Jacobsen ED, Fisher DC, LaCasce AS, Ho VT, Cutler CS, Koreth J, Soiffer RJ, Antin JH, Berliner N, Nikiforow S
Breast Cancer Research and Treatment
Erick TK, Daley H, Campbell M, Colson Y, Mihm M, Zakka LR, Barry W, Winer EP, Dranoff G, Overmoyer B
Cancer
Ligibel JA, Dieli-Conwright C
Cancer Immunology Research
Gil Del Alcazar CR, Aleckovic M, Rojas Jimenez E, Harper NW, Oliphant MU, Xie S, Krop ED, Lulseged B, Keenan TE, Van Allen EM, Tolaney SM, Freeman GJ, Dillon DA, Muthuswamy SK, Polyak K
Cell Reports
Hypoxic, Glycolytic Metabolism is a Vulnerability of B-Acute Lymphoblastic Leukemia-Initiating Cells
Morris V, Wang D, Li Z, Marion W, Hughes T, Sousa P, Harada T, Sui SH, Naumenko S, Kalfon J, Sensharma P, Pikman Y, Harris M, Orkin SH, Koehler AN, Shalek AK, North TE, Pimkin M, Daley GQ, Rowe RG
Cell Systems
Sparse Dictionary Learning Recovers Pleiotropy from Human Cell Fitness Screens
Pan J, Kwon JJ, Talamas JA, Borah AA, Vazquez F, Boehm JS, Tsherniak A, Zitnik M, McFarland JM, Hahn WC
Clinical Cancer Research
Improved T Cell Immunity Following Neoadjuvant Chemotherapy in Ovarian Cancer
Liu M, Tayob N, Penter L, Sellars M, Tarren A, Chea V, Carulli I, Huang T, Li S, Cheng SC, Le P, Frackiewicz L, Fasse J, Qi C, Liu JF, Stover EH, Curtis J, Livak KJ, Neuberg D, Matulonis UA, Wu CJ, Keskin DB, Konstantinopoulos PA
Clinical Cancer Research
Linking Genotype to Phenotype: Bench to Bedside
George S, Bertagnolli MM
EMBO Journal
Atossa: A Royal Link Between OXPHOS Metabolism and Macrophage Migration
Latorre-Muro P, Puigserver P
Expert Review of Anticancer Therapy
Enfortumab Vedotin-Ejfv for the Treatment of Advanced Urothelial Carcinoma
Mantia CM, Sonpavde G
Expert Review of Anticancer Therapy
Zanubrutinib for the Treatment of Adults with Waldenström Macroglobulinemia
Sarosiek S, Sermer D, Branagan AR, Treon SP, Castillo JJ
Haematologica
Gibson CJ, Koreth J
Haematologica
Rambaldi B, Kim HT, Arihara Y, Asano T, Reynolds C, Manter M, Halpern M, Weber A, Koreth J, Cutler C, Gooptu M, Nikiforow S, Ho VT, Antin JH, Romee R, Soiffer RJ, Ritz J
Journal of Integrative and Complementary Medicine
Skin Temperature of Acupoints in Health and Disease: A Systematic Review
Yang E, Lu W, Muñoz-Vergara D, Goldfinger E, Kaptchuk TJ, Napadow V, Ahn AC, Wayne PM
Journal of Neuro-Oncology
Survival Outcomes Associated with MGMT Promoter Methylation and Temozolomide in Gliosarcoma Patients
Kavouridis VK, Ligon KL, Wen PY, Iorgulescu JB
Journal of Psychosocial Oncology
Chevalier LL, Fine E, Sharma A, Zhou ES, Recklitis CJ
Journal of Virology
Nguyen HT, Qualizza A, Anang S, Zhao M, Zou S, Zhou R, Wang Q, Zhang S, Sodroski JG
JAMA Psychiatry
Zhou ES
Lung Cancer
Adjust, Don't Avoid: The Need for Risk-Based CT Screening in Nonsmoking Populations
Swami N, Chen TY, Duma N
Nature Cancer
Bondeson DP, Paolella BR, Asfaw A, Rothberg MV, Skipper TA, Langan C, Mesa G, Gonzalez A, Surface LE, Ito K, Kazachkova M, Colgan WN, Warren A, Dempster JM, Krill-Burger JM, Ericsson M, Tang AA, Fung I, Chambers ES, Abdusamad M, Dumont N, Doench JG, Piccioni F, Root DE, Boehm J, Hahn WC, Mannstadt M, McFarland JM, Vazquez F, Golub TR
Neuro-Oncology
Trends in Location of Death for Individuals with Primary Brain Tumors in the United States
Aizer AA, Bi WL, Haas-Kogan D, Rahman R
Protein Cell
Wang JH
Science Advances
Tanton H, Sewastianik T, Seo HS, Remillard D, Pierre RS, Bala P, Aitymbayev D, Dennis P, Adler K, Geffken E, Yeoh Z, Vangos N, Garbicz F, Scott D, Sethi N, Bradner J, Dhe-Paganon S, Carrasco RD
Trends in Cell Biology
Moonlighting Translation Factors: Multifunctionality Drives Diverse Gene Regulation
Farache D, Antine SP, Lee ASY