Skip to main content

Dana-Farber Research Publication 5.15.2022

Welcome to Dana-Farber's Research News

View Archive Newsletters

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:


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.



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

Evolving Role of Prostate-Specific Membrane Antigen-Positron Emission Tomography in Metastatic Hormone-Sensitive Prostate Cancer: More Questions than Answers?

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

Reply to L. Marandino et al

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

DUB to the Rescue

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.



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.

Antibody-Mediated Blockade of the IL23 Receptor Destabilizes Intratumoral Regulatory T Cells and Enhances Immunotherapy

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.



Repetitive DNA in Disease

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

Sugar-Sweetened Beverage and Sugar Consumption and Colorectal Cancer Incidence and Mortality According to Anatomic Subsite

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

EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified: 2022 Update on Diagnosis, Risk-Stratification and Management

Castillo JJ


Annals of Surgical Oncology

ASO Visual Abstract: Variation in Deescalated Axillary Surgical Practices in Older Women with Early-Stage Breast Cancer

Minami CA, Jin G, Schonberg MA, Freedman RA, King TA, Mittendorf EA


Blood Advances

A Phase 1 Study of Donor Regulatory T-Cell Infusion Plus Low-Dose Interleukin-2 for Steroid-Refractory Chronic Graft-vs-Host Disease

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

Favorable Outcomes Following Allogeneic Transplantation in Adults with Hemophagocytic Lymphohistiocytosis

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

The Feasibility of Using an Autologous GM-CSF-Secreting Breast Cancer Vaccine to Induce Immunity in Patients with Stage II-III and Metastatic Breast Cancers

Erick TK, Daley H, Campbell M, Colson Y, Mihm M, Zakka LR, Barry W, Winer EP, Dranoff G, Overmoyer B



Attention to Diet, Exercise, and Weight in Oncology Care: Results of an American Society of Clinical Oncology National Patient Survey

Ligibel JA, Dieli-Conwright C


Cancer Immunology Research

Insights into Immune Escape During Tumor Evolution and Response to Immunotherapy Using a Rat Model of Breast Cancer

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



Molecular Assessment and the Current Limits of Post-Transplant Prognostication for Chronic Myelomonocytic Leukemia

Gibson CJ, Koreth J



Phenotypic and Functional Characterization of the CD6-ALCAM T Cell Costimulatory Pathway After Allogeneic Cell Transplantation

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

Evaluating the Sleep Treatment Education Program (STEP-1): A Single-Session Educational Workshop Addressing Insomnia in Cancer Survivors

Chevalier LL, Fine E, Sharma A, Zhou ES, Recklitis CJ


Journal of Virology

Functional and Highly Cross-Linkable HIV-1 Envelope Glycoproteins Enriched in a Pretriggered Conformation

Nguyen HT, Qualizza A, Anang S, Zhao M, Zou S, Zhou R, Wang Q, Zhang S, Sodroski JG


JAMA Psychiatry

Effect of Culturally Tailored, Internet-Delivered Cognitive Behavioral Therapy for Insomnia in Black Women: A Randomized Clinical Trial

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

Phosphate Dysregulation Via the XPR1-KIDINS220 Protein Complex is a Therapeutic Vulnerability in Ovarian 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



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

The Early Days of Structural Biology at the Beijing Institute of Biophysics: In Memory of Professor Zhengjiong Lin (1935-2022)

Wang JH


Science Advances

A Novel b-catenin/BCL9 Complex Inhibitor Blocks Oncogenic Wnt Signaling and Disrupts Cholesterol Homeostasis in Colorectal Cancer

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