This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from September 16 - September 30.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing [email protected].
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Blood
Mechanisms of Immune Escape and Extramedullary Tropism in Leukemia Cutis
Maurer K, Cieri N, Lu W, Lyu H, Li S, Livak KJ, Ritz J, Davids MS, Garcia JS, Soiffer RJ, Wu CJ
The mechanisms that lead to extramedullary tropism of acute myeloid leukemia (eAML) remain obscure and no specific therapeutic approaches for this entity exist. As the long-term survival of eAML is poor, a deeper understanding of the immune microenvironment and leukemia phenotypes underlying this entity is warranted. Here, we performed bulk and single-cell transcriptome profiling of 23 eAML biopsies from 10 patients with isolated extramedullary disease in skin and subcutaneous tissue. Unlike normal healthy skin, we found leukemia cutis to be heavily immune-infiltrated; in cases of extramedullary relapse following allogeneic stem cell transplantation, >90% of T/NK cells were donor-derived. eAML-associated T cells expressed a clear signature of T cell exhaustion, dissimilar to leukemia-associated immune populations in bone marrow relapse (n=7), but related to acute and chronic skin inflammation. Further, HLA class II was down-regulated in 4 of 7 leukemia cutis specimens, consistent with an immune escape phenotype in cases of eAML. Extramedullary and bone marrow-resident leukemia cells differed with regard to the expression of 8 homing receptor molecules (ICAM1 (encoding CD54), PECAM1 (CD31), ITGA4, ITGA6, ITGAL, ITGB4, ITGA5, and ITGAV). Serial samples obtained from one leukemia cutis case throughout consecutive immune checkpoint blockade with ipilimumab followed by nivolumab showed a consistently high degree of overlap between local and circulating T cell receptor (TCR) sequences, suggesting that only a minority of eAML-associated T cells are leukemia-specific. Our analysis reveals eAML to associate with complex changes in leukemia and T cell gene expression profiles that suggest multiple potential avenues for therapeutic targeting.
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Cell
A Multi-Adjuvant Personal Neoantigen Vaccine Generates Potent Immunity in Melanoma
Blass E, Keskin DB, Tu CR, Forman C, Vanasse A, Sax HE, Shim B, Chea V, Kim N, Carulli I, Southard J, Lyu H, Lu W, Rickles-Young M, Afeyan AB, Olive O, Mehndiratta A, Greenslade H, Shetty K, Baginska J, Gomez Diaz I, Nau A, Pfaff KL, Gans A, Ranasinghe S, Buchbinder EI, Sussman TA, Insco ML, Yoon CH, Rodig SJ, Shukla SA, Li S, Aster JC, Braun DA, Cibulskis C, Hacohen N, Neuberg DS, Giobbie-Hurder A, Livak KJ, Fritsch EF, Oliveira G, Simon JM, Wu CJ, Ott PA
Personalized neoantigen-targeting vaccines have demonstrated great promise; however, improved immunogenicity is still needed. Since antigen availability and effective T cell priming are critical for maximal immunogenicity, we tested a synthetic long peptide vaccine formulated with Montanide, poly-ICLC, and locally administered ipilimumab in addition to systemic nivolumab in 10 patients with melanoma. These personalized vaccines generated de novo ex vivo T cell responses against the majority of immunizing neoepitopes in all 9 fully vaccinated patients and ex vivo CD8+ T cell responses in 6 of 9. Vaccination induced hundreds of circulating and intratumoral T cell receptor (TCR) clonotypes that were distinct from those arising after PD-1 inhibition. By linking the vaccine neoantigen specificity of T cell clonotypes with single-cell phenotypes in tumors, we demonstrate remodeling of the intratumoral T cell repertoire following vaccination. These observations show that multi-pronged immune adjuvanticity can boost T cell responses to neoantigen-targeting vaccines.
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Journal of Clinical Oncology
Inotuzumab Ozogamicin Then Blinatumomab for Older Adults with Newly Diagnosed B-Cell ALL: Alliance Study A041703 Cohort 1 Results
Stone RM
PURPOSE: Older patients with ALL receiving conventional chemotherapy have poor survival due to toxic death and relapse. We hypothesized that a chemotherapy-free, targeted regimen using the anti-CD22 antibody-calicheamicin conjugate inotuzumab ozogamicin followed by the bispecific anti-CD19/CD3 T-cell engager blinatumomab would reduce toxic death and yield high rates of prolonged remission and survival.
METHODS: Eligible patients were age 60 years and older with untreated, Philadelphia chromosome (Ph)-negative, CD22-positive, B-cell ALL. Patients received up to two cycles of inotuzumab ozogamicin followed by four or five cycles of blinatumomab with intrathecal methotrexate CNS prophylaxis. The primary end point was 1-year event-free survival (EFS).
RESULTS: The 33 eligible patients had a median age of 71 years (range, 60-84) and a median CD22 expression of 92% (range, 21%-100%). Eight (24%) had previous chemotherapy or radiation for other cancers, six for multiple myeloma. The composite complete remission rate was 85% after two cycles of inotuzumab ozogamicin and 97% by the end of two cycles of blinatumomab. At a median follow-up of 30 months, the 1-year EFS and overall survival were 75% (95% CI, 61 to 92) and 85% (95% CI, 73 to 98), respectively. EFS was shorter with lower CD22 expression or detectable measurable residual disease at any time point.
CONCLUSION: Inotuzumab ozogamicin then blinatumomab without maintenance chemotherapy in older patients with untreated, Ph-negative, CD22-positive, B-cell ALL yields a high remission rate and excellent EFS. Given the lack of standard, safe, and effective therapies in this population, the regimen should be considered a standard treatment option.
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Journal of Clinical Oncology
Stereotactic Radiosurgery in Patients with Small Cell Lung Cancer and 1-10 Brain Metastases: A Multi-Institutional, Phase II, Prospective Clinical Trial
Aizer AA, Tanguturi SK, Shi DD, Catalano PJ, Shin KY, Ricca I, Johnson M, Benham G, Kozono DE, Mak RH, Hertan L, Chipidza F, Krishnan M, Pashtan I, Peng L, Qian JM, Shiloh RY, Sands J, Wen PY, Haas-Kogan DA, Rahman R
PURPOSE: Stereotactic radiation (SRS/SRT) as opposed to whole-brain radiation (WBRT) represents the standard of care for patients with a limited number of brain metastases given the relatively favorable toxicity profile associated with stereotactic treatment. However, in patients with small cell lung cancer (SCLC), WBRT remains standard because of a lack of prospective data supporting SRS/SRT and concerns related to intracranial progression and neurologic death when WBRT is omitted. We conducted a single-arm, multicenter, phase II trial of SRS/SRT in patients with SCLC and 1-10 brain metastases to assess neurologic death rates relative to historical controls managed with WBRT (ClinicalTrials.gov identifier: NCT03391362).
METHODS: Patients were eligible if they had SCLC or an extrathoracic small cell primary and 1-10 brain metastases. Previous brain-directed radiation including prophylactic cranial irradiation was not permitted. Neurologic death was defined as marked, progressive, radiographic brain progression accompanied by corresponding neurologic symptomatology without systemic disease progression or systemic symptoms of a life-threatening nature. Close imaging-based surveillance of the brain post-SRS/SRT was used.
RESULTS: Between February 2018 and April 2023, 100 patients were enrolled. The median number of brain metastases was 2 (IQR, 1-4; range, 1-10). The median overall survival was 10.2 months; only 22% of patients required salvage WBRT. In total, 20 neurologic deaths were observed, relative to 64 non-neurologic deaths. The neurologic death rate at 1 year was 11.0% (95% CI, 5.8 to 18.1); the historical rate in patients managed with WBRT was 17.5%.
CONCLUSION: Our prospective, multi-institutional study demonstrated low rates of neurologic death when SRS/SRT as opposed to WBRT is used in patients with SCLC and 1-10 brain metastases who are surveilled closely post-treatment, supporting the utility of stereotactic approaches in this population.
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Journal of the National Cancer Institute
Sex Differences in Chemotherapy Completion, Toxicities, and Survival in Colon Cancer: An Analysis of 2201 Patients from CALGB/SWOG 80702 (alliance)
Ma C, Ng K, Meyerhardt JA
BACKGROUND: Completing adjuvant chemotherapy and reducing toxicities are critical tenets to maximize survival after colon cancer diagnosis. Sex, as a biological variable, may impact colon cancer chemotherapy completion, toxicities, and survival differently.
METHODS: From an NCI-sponsored trial conducted among patients with stage III colon cancer (CALGB/SWOG 80702), we included 2201 patients receiving standard adjuvant chemotherapy FOLFOX (fluorouracil, leucovorin, and oxaliplatin). We calculated relative dose intensity (RDI) to indicate chemotherapy completion and considered reduced RDI (RDI <85%) as a clinically significant deviation from standard FOLFOX. Using NCI's Common Terminology Criteria for Adverse Events (AE), we defined severe AE (grade ≥3) as the occurrence of any following event including neutrophils decrease, nausea, platelets decrease, hypertension, peripheral neuropathy, diarrhea, fatigue, gastritis, creatinine increase, gastric ulcer, myocardial ischemia, and cerebral ischemia. The primary survival outcome was disease-free survival (time from enrollment to colon cancer recurrence or death from any cause), and secondary survival outcomes were recurrence-free and overall survival.
RESULTS: Compared to males, females were at significantly higher risks of experiencing reduced RDI (adjusted OR 1.59 [1.29-1.96]; P < .001) and severe AE (adjusted OR: 1.72 [1.41-2.11]; P < .001). Yet, females had significantly better disease-free survival (adjusted HR: 0.72 [0.59, 0.87]; P < .001) as well as better recurrence-free and overall survival.
CONCLUSIONS: Our findings suggested that females with colon cancer are more likely to have worse chemotherapy completion and more severe AE, but they have better survival. Sex, as a biological variable, warrants further consideration in chemotherapy administration and survivorship management after colon cancer diagnosis.
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Nature
Covariation MS Uncovers a Protein that Controls Cysteine Catabolism
Xiao H, Ordonez M, Fink EC, Covington TA, Woldemichael HB, Jain MS, Wei SM, Burger N, Sharif MA, Wang Y, Petrocelli JJ, Blackmore K, Smythers AL, Zhang B, Gilbert M, Cheong H, Khetarpal SA, Smith A, Bogoslavski D, Lei Y, Vaites LP, Donovan KA, Huttlin EL, Mills EL, Fischer ES, Chouchani ET
The regulation of metabolic processes by proteins is fundamental to biology and yet is incompletely understood. Here we develop a mass spectrometry (MS)-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This method recapitulates protein-metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation while nominating 3,542 previously undescribed relationships. With this foundation, we identify a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein LRRC58. We show that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the catabolic shunt of cysteine to taurine1. Cysteine abundance regulates LRRC58-mediated CDO1 degradation, and depletion of LRRC58 is sufficient to stabilize CDO1 to drive consumption of cysteine to produce taurine. Taurine has a central role in cholesterol handling, promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes increases cysteine flux to taurine and lowers hepatic cholesterol in mice. Uncovering the mechanism of LRRC58 control over cysteine catabolism exemplifies the utility of covariation MS to identify modes of protein regulation of metabolic processes.
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Nature Communications
In Vivo CRISPR Screening in Head and Neck Cancer Reveals Uchl5 as an Immunotherapy Target
Fu C, Chinai JM, Kim SY, Kammula AV, Perera JJ, Jiang A, Tiwari P, Kistler EN, Colvin KJ, Dubrot J, Anderson S, Fetterman RA, Chuong CL, Lane-Reticker SK, Cheruiyot CK, Muscato AJ, Griffin GK, Bernstein BE, Egloff AM, Yates KB, Uppaluri R, Manguso RT
Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a significant unmet need for enhancing immunotherapy response given current modest efficacy. Here, we perform an in vivo CRISPR screen in an HNSCC mouse model to identify immune evasion genes. We identify several regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of Uchl5 in tumors increases CD8+ T cell infiltration and improved ICB responses. Uchl5 deficiency attenuates extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional programs, which contribute to stromal desmoplasia, a histologic finding we describe as associated with reduced anti-PD1 response in human HNSCCs. COL17A1, a collagen highly and specifically expressed in HNSCC, mediates in part Uchl5-mediated immune evasion. Our findings suggest an unappreciated role for UCHL5 in promoting EMT in HNSCC and highlight ECM modulation as a strategy to improve immunotherapy responses.
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Nature Communications
Structural Insights into Chemoresistance Mutants of BCL-2 and Their Targeting by Stapled BAD BH3 Helices
DeAngelo TM, Adhikary U, Korshavn KJ, Seo HS, Brotzen-Smith CR, Camara CM, Dhe-Paganon S, Bird GH, Walensky LD
BCL-2 is a central regulator of apoptosis and inhibits cell death by sequestering pro-apoptotic BH3 alpha-helices within a hydrophobic surface groove. While venetoclax, a BH3-mimetic drug, has transformed the treatment of BCL-2-driven malignancies, its efficacy is increasingly limited by acquired resistance mutations that disrupt small-molecule binding yet preserve anti-apoptotic function-reflecting a remarkable structural adaptation. Here, we employ hydrocarbon-stapled alpha-helices derived from the BAD BH3 motif as conformation-sensitive molecular probes to investigate this therapeutic challenge. The stapled peptides not only retain high-affinity binding to all BCL-2 variants but also show enhanced potency to select venetoclax-resistant mutants. Structural analyses, including X-ray crystallography and hydrogen-deuterium exchange mass spectrometry (HDX MS), demonstrate that these stapled helices restore native BH3 engagement by reversing the conformational consequences of resistance mutations. Notably, we identify a serendipitous interaction between the α3-α4 region of BCL-2 and hydrocarbon staple, which further compensates for altered groove conformation and contributes to mutant binding affinity. Together, these findings offer mechanistic insights into BCL-2 drug resistance and reveal a blueprint for designing next-generation inhibitors that overcome this clinically significant barrier to durable treatment responses.
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Nature Genetics
Rapid Epigenomic Classification of Acute Leukemia
Steinicke TL, Benfatto S, Capilla-Guerra MR, Monteleone AB, Young JH, Shankar S, Michaels PD, Tsai HK, Good JD, Kreso A, van Galen P, Schliemann C, Chen EC, Griffin GK, Hovestadt V
Acute leukemia requires precise molecular classification and urgent treatment. However, standard-of-care diagnostic tests are time-intensive and do not capture the full spectrum of acute leukemia heterogeneity. Here, we developed a framework to classify acute leukemia using genome-wide DNA methylation profiling. We first assembled a comprehensive reference cohort (n = 2,540 samples) and defined 38 methylation classes. Methylation-based classification matched standard-pathology lineage classification in most cases and revealed heterogeneity in addition to that captured by genetic categories. Using this reference, we developed a neural network (MARLIN; methylation- and AI-guided rapid leukemia subtype inference) for acute leukemia classification from sparse DNA methylation profiles. In retrospective cohorts profiled by nanopore sequencing, high-confidence predictions were concordant with conventional diagnoses in 25 out of 26 cases. Real-time MARLIN classification in patients with suspected acute leukemia provided accurate predictions in five out of five cases, which were typically generated within 2 h of sample receipt. In summary, we present a framework for rapid acute leukemia classification that complements and enhances standard-of-care diagnostics.
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New England Journal of Medicine
An Aspirin a Day for Improved Colorectal Cancer Outcomes
Meyerhardt JA
The painkilling, antipyretic, and antiinflammatory properties of aspirin have been known for centuries. The understanding that aspirin targets cyclooxygenase-1 (COX-1) (also known as prostaglandin-endoperoxide synthase 2 [PTGS1]) and COX-2 (also known as PTGS2), which are key enzymes required for prostaglandin synthesis, provided a rationale for using aspirin to treat thrombosis. Case–control studies and prospective cohort studies showed that aspirin may reduce the risk of premalignant colorectal adenoma and colorectal cancer. Data from randomized trials comparing aspirin and placebo with regard to the primary end points or secondary end points (as in studies of cardiovascular disease prevention) of colorectal adenoma and colorectal cancer support epidemiologic data.1 In 2016, the U.S. Preventive Services Task Force recommended low-dose aspirin for the primary prevention of colorectal cancer and cardiovascular disease in adults who are 50 to 59 years of age and have a 10-year cardiovascular disease risk of at least 10%. The guidance was revised in 2022 because the preventive effects of aspirin were unclear, on the basis of the results of simulation modeling and data from the ASPREE (Aspirin in Reducing Events in the Elderly) trial, which showed that daily aspirin therapy did not lead to a lower rate of disability-free survival among older adults than placebo.
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Proceedings of the National Academy of Sciences of the U.S.A.
Making Sense of Low-Complexity Domains: The 2025 Lasker Basic Science Award
Kaelin WG Jr
Up to 10 to 20% of the proteome contains regions with much lower amino acid diversity than would be expected by chance. This year's Lasker Basic Science Award is given to Steven McKnight and Dirk Görlich for their pioneering work on such low-complexity domains (LCDs). They showed, using a variety of elegant approaches, that such LCDs can form homotypic and heterotypic interactions that lead to reversible phase separations in cells. These phase separations, which in the laboratory manifest as hydrogels and in cells as membrane free structures (liquid condensates) such as P bodies and stress granules, form hubs for molecular processes such as transcription and messenger RNA (mRNA) splicing and also underlie the selectivity of nuclear pore complexes (NPCs), which act a barriers to large molecules unless they are escorted by specific LCD containing nuclear transporters that interact with LCD containing nucleoporins within NPC channels. Naturally occurring LCD mutations linked to neurodegeneration and other diseases cause the formation of irreversible (rather than reversible) LCD polymers, resulting in insoluble, amyloid-like, fibrils, underscoring the critical importance of these domains.
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Science
Deazaguanylation is a Nucleobase-Protein Conjugation Required for Type IV CBASS Immunity
Wassarman DR, Paulo JA, Gygi SP, Kranzusch PJ
7-Deazapurines are nucleobase analogs essential for nucleic acid modifications in nearly all cellular life. In this study, we discovered a role for 7-deazapurines in protein modification within type IV cyclic oligonucleotide-based antiviral signaling system (CBASS) antiphage defense and defined functions for CBASS ancillary proteins Cap9 and Cap10 in nucleobase-protein conjugation. A structure of Cap10 revealed a transfer RNA transglycosylase family enzyme remodeled to bind a partner cGAS/DncV-like nucleotidyltransferase that is modified with an N-terminal 7-amido-7-deazaguanine (NDG) nucleobase. A structure of Cap9 explained how this QueC-like enzyme co-opts a 7-deazapurine biosynthetic reaction to install NDG. We show that Cap9, Cap10, and protein deazaguanylation are essential for host defense against phage infection. Our results define a 7-deazapurine protein modification and explain how nucleobase biosynthetic machinery has been repurposed for antiviral immunity.
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Breast Cancer Research
Neoadjuvant Therapy with Eribulin, Doxorubicin and Cyclophosphamide for Patients with HER2-Negative Inflammatory Breast Cancer: A Phase II Study
Fanucci K, Yeh ED, Shi R, Qin L, Bay CP, DiLullo M, Patel A, Moore M, Herbert ZT, Harrison BT, Nakhlis F, Bellon J, Warren L, Guerriero JL, Tolaney SM, Regan M, Overmoyer B, Van Laere S, Lynce F
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Cell Chemical Biology
Pharmacologic Interrogation of USP28 Cellular Function in p53 Signaling
Bratt AS, Kilgas S, Tarazona Guzman MI, Magin RS, Jaen Maisonet I, Starnbach CA, Teh WP, Varca AC, Hu B, Tarazona Guzman E, Seo HS, Dhe-Paganon S, Girardi NM, Adelmant G, Marto JA, Chowdhury D, Buhrlage SJ
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Cell Reports
Integrative Genomic Identification of Therapeutic Targets for Pancreatic Cancer
Guo JA, Gong D, Evans K, Takahashi K, Shiau C, Wu WW, Chugh S, Kapner KS, Dilly J, Chen P, Smith EL, Mancias JD, Vazquez F, Singh H, Hwang WL, Aguirre AJ
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Journal of Thoracic Oncology
Brief Report: Critical Role for DNA-Based Sequencing in Discriminating Distinct Primary Lung Cancers with Different MET Exon 14 Skipping Mutations
Pecci F, Ricciuti B, Nakazawa S, Di Federico A, Aldea M, Garbo E, Santo V, Gariazzo E, Makarem M, Haradon D, Odintsov I, Yang SR, Figueroa PAU, Nishino M, Jänne PA, Sholl LM
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Nature Cardiovascular Research
Cardiac Adaptation to Endurance Exercise Training Requires Suppression of GDF15 via PGC-1α
Khetarpal SA, Li H, Vitale T, Rhee J, Challa S, Castro C, Pabel S, Sun Y, Liu J, Bogoslavski D, Vargas-Castillo A, Smythers AL, Blackmore KA, Grauvogel L, Mittenbühler MJ, Khandekar MJ, Curtin C, Narvaez-Paliza JM, Wang C, Houstis NE, Sprenger HG, Jurgens SJ, Biddinger KJ, Kuznetsov A, Freeman R, Ellinor PT, Nahrendorf M, Paulo JA, Gygi SP, Dumesic PA, Asnani A, Aragam KG, Puigserver P, Roh JD, Spiegelman BM
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Stem Cell Reports
Satellite Glial Contact Enhances Differentiation and Maturation of Human iPSC-Derived Sensory Neurons
LeBlang CJ, Pazyra-Murphy MF, Silagi ES, Dasgupta S, Tsolias M, Miller T, Petrova V, Zhen S, Woolf CJ, Tasdemir-Yilmaz O, Segal RA
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Transplantation and Cellular Therapy
Expression of HLA-B*35 is Associated with an Increased Risk of CMV Viremia and Clinically Significant CMV Infection following PTCy-based Hematopoietic Cell Transplantation
Little JS, Hebert KM, Neuberg DS, Nikiforow S, Gooptu M, Shapiro RM, Koreth J, Antin JH, Cutler C, Soiffer RJ, Ritz J, Romee R, Ho VT, Issa NC, Baden LR, Duléry R, Prockop SE
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