Publications by authors named "Tiffany Tanaka"

11 Publications

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Clonal hematopoiesis driven by DNMT3A and TET2 mutations: role in monocyte and macrophage biology and atherosclerotic cardiovascular disease.

Curr Opin Hematol 2022 Jan;29(1):1-7

Sulpizio Cardiovascular Center, Division of Cardiology, University of California San Diego, La Jolla, California, USA.

Purpose Of Review: Clonal hematopoiesis of indeterminate potential (CHIP), defined by the presence of somatic mutations in hematopoietic cells, is associated with advanced age and increased mortality due to cardiovascular disease. Gene mutations in DNMT3A and TET2 are the most frequently identified variants among patients with CHIP and provide selective advantage that spurs clonal expansion and myeloid skewing. Although DNMT3A and TET2 appear to have opposing enzymatic influence on DNA methylation, mounting data has characterized convergent inflammatory pathways, providing insights to how CHIP may mediate atherosclerotic cardiovascular disease (ASCVD).

Recent Findings: We review a multitude of studies that characterize aberrant inflammatory signaling as result of DNMT3A and TET2 deficiency in monocytes and macrophages, immune cells with prominent roles in atherosclerosis. Although specific DNA methylation signatures associated with these known epigenetic regulators have been identified, many studies have also characterized diverse modulatory functions of DNTM3A and TET2 that urge cell and context-specific experimental studies to further define how DNMT3A and TET2 may nonenzymatically activate inflammatory pathways with clinically meaningful consequences.

Summary: CHIP, common in elderly individuals, provides an opportunity understand and potentially modify age-related chronic inflammatory ASCVD risk.
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http://dx.doi.org/10.1097/MOH.0000000000000688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639635PMC
January 2022

Adoptive transfer of neoantigen-specific T-cell therapy is feasible in older patients with higher-risk myelodysplastic syndrome.

Cytotherapy 2021 03 3;23(3):236-241. Epub 2020 Dec 3.

University of California San Diego Moores Cancer Center, La Jolla, California, USA. Electronic address:

Background: Myelodysplastic syndromes (MDS) represent the most common type of acquired bone marrow failure in adults and is characterized by ineffective maturation of myeloid precursor cells and peripheral cytopenias associated with higher rates of infection, bleeding and transfusion dependence. In higher-risk patients with MDS who relapse or do not respond after standard hypomethylating agent (HMA) therapy, the 2-year survival rate is 15%.

Methods: Here the authors report the feasibility and safety of a novel experimental T-cell therapy called personalized adoptive cell therapy, which selects, immunizes and expands T cells against MDS-specific mutations and is targeted to patient-specific tumor cell neoantigens. Somatic mutations serve as the pathogenic drivers of cancer, including MDS, as these transformative genetic mutations may generate novel immunogenic proteins (i.e., neopeptides and possible neoantigens) that may be targeted therapeutically.

Results: The authors demonstrate that the adaptive immune system can be trained ex vivo to recognize neopeptides as neoantigens and that the infusion of culture-expanded, neoantigen-immunized autologous T cells has been feasible and safe in the three patients treated to date.

Discussion: The authors report on early results from their first-in-human phase 1 clinical trial that aims to assess the safety and tolerability of this novel form of adoptive T-cell immunotherapy for HMA-refractory patients with higher-risk MDS.
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http://dx.doi.org/10.1016/j.jcyt.2020.11.003DOI Listing
March 2021

In vitro induction of neoantigen-specific T cells in myelodysplastic syndrome, a disease with low mutational burden.

Cytotherapy 2021 04 28;23(4):320-328. Epub 2020 Nov 28.

PersImmune, Inc., San Diego, California, USA. Electronic address:

Therapies that utilize immune checkpoint inhibition work by leveraging mutation-derived neoantigens and have shown greater clinical efficacy in tumors with higher mutational burden. Whether tumors with a low mutational burden are susceptible to neoantigen-targeted therapy has not been fully addressed. To examine the feasibility of neoantigen-specific adoptive T-cell therapy, the authors studied the T-cell response against somatic variants in five patients with myelodysplastic syndrome (MDS), a malignancy with a very low tumor mutational burden. DNA and RNA from tumor (CD34) and normal (CD3) cells isolated from the patients' blood were sequenced to predict patient-specific MDS neopeptides. Neopeptides representing the somatic variants were used to induce and expand autologous T cells ex vivo, and these were systematically tested in killing assays to determine the proportion of neopeptides yielding neoantigen-specific T cells. The authors identified a total of 32 somatic variants (four to eight per patient) and found that 21 (66%) induced a peptide-specific T-cell response and 19 (59%) induced a T-cell response capable of killing autologous tumor cells. Of the 32 somatic variants, 11 (34%) induced a CD4 response and 11 (34%) induced a CD8 response that killed the tumor. These results indicate that in vitro induction of neoantigen-specific T cells is feasible for tumors with very low mutational burden and that this approach warrants investigation as a therapeutic option for such patients.
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http://dx.doi.org/10.1016/j.jcyt.2020.10.003DOI Listing
April 2021

5-Azacytidine Transiently Restores Dysregulated Erythroid Differentiation Gene Expression in TET2-Deficient Erythroleukemia Cells.

Mol Cancer Res 2021 03 10;19(3):451-464. Epub 2020 Nov 10.

Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California.

DNA methyltransferase inhibitors (DNMTI) like 5-Azacytidine (5-Aza) are the only disease-modifying drugs approved for the treatment of higher-risk myelodysplastic syndromes (MDS), however less than 50% of patients respond, and there are no predictors of response with clinical utility. Somatic mutations in the DNA methylation regulating gene () are associated with response to DNMTIs, however the mechanisms responsible for this association remain unknown. Using bisulfite padlock probes, mRNA sequencing, and hydroxymethylcytosine pull-down sequencing at several time points throughout 5-Aza treatment, we show that loss particularly influences DNA methylation (5mC) and hydroxymethylation (5hmC) patterns at erythroid gene enhancers and is associated with downregulation of erythroid gene expression in the human erythroleukemia cell line TF-1. 5-Aza disproportionately induces expression of these down-regulated genes in TET2KO cells and this effect is related to dynamic 5mC changes at erythroid gene enhancers after 5-Aza exposure. We identified differences in remethylation kinetics after 5-Aza exposure for several types of genomic regulatory elements, with distal enhancers exhibiting longer-lasting 5mC changes than other regions. This work highlights the role of 5mC and 5hmC dynamics at distal enhancers in regulating the expression of differentiation-associated gene signatures, and sheds light on how 5-Aza may be more effective in patients harboring mutations. IMPLICATIONS: TET2 loss in erythroleukemia cells induces hypermethylation and impaired expression of erythroid differentiation genes which can be specifically counteracted by 5-Azacytidine, providing a potential mechanism for the increased efficacy of 5-Aza in TET2-mutant patients with MDS. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/3/451/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925369PMC
March 2021

DNA methylation identifies genetically and prognostically distinct subtypes of myelodysplastic syndromes.

Blood Adv 2019 10;3(19):2845-2858

Department of Biomedical Sciences.

Recurrent mutations implicate several epigenetic regulators in the early molecular pathobiology of myelodysplastic syndromes (MDS). We hypothesized that MDS subtypes defined by DNA methylation (DNAm) patterns could enhance our understanding of MDS disease biology and identify patients with convergent epigenetic profiles. Bisulfite padlock probe sequencing was used to measure DNAm of ∼500 000 unique cytosine guanine dinucleotides covering 140 749 nonoverlapping regulatory regions across the genome in bone marrow DNA samples from 141 patients with MDS. Application of a nonnegative matrix factorization (NMF)-based decomposition of DNAm profiles identified 5 consensus clusters described by 5 NMF components as the most stable grouping solution. Each of the 5 NMF components identified by this approach correlated with specific genetic abnormalities and categorized patients into 5 distinct methylation clusters, each largely defined by a single NMF component. Methylation clusters displayed unique differentially methylated regulatory loci enriched for active and bivalent promoters and enhancers. Two clusters were enriched for samples with complex karyotypes, although only one had an increased number of mutations. Each of the 3 most frequently mutated splicing factors, , , and , was enriched in different clusters. Mutations of , , and were coenriched in the containing cluster. In multivariate analysis, methylation cluster membership remained independently associated with overall survival. Targeted DNAm profiles identify clinically relevant subtypes of MDS not otherwise distinguished by mutations or clinical features. Patients with diverse genetic lesions can converge on common DNAm states with shared pathogenic mechanisms and clinical outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2019000192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784525PMC
October 2019

Acute myeloid leukaemia evolving from essential thrombocythaemia with marked KMT2A amplification as a homogenously staining region.

Br J Haematol 2019 08 28;186(4):509. Epub 2019 May 28.

Division of Laboratory and Genomic Medicine, Departments of Pathology, University of California San Diego Health Sciences, La Jolla, CA, USA.

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http://dx.doi.org/10.1111/bjh.15985DOI Listing
August 2019

Management of cancer-associated anemia with erythropoiesis-stimulating agents: ASCO/ASH clinical practice guideline update.

Blood Adv 2019 04;3(8):1197-1210

Western University, London, ON, Canada.

Purpose: To update the American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer.

Methods: PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and meta-analyses of RCTs in patients with cancer published from January 31, 2010, through May 14, 2018. For biosimilar ESAs, the literature search was expanded to include meta-analyses and RCTs in patients with cancer or chronic kidney disease and cohort studies in patients with cancer due to limited RCT evidence in the cancer setting. ASCO and ASH convened an Expert Panel to review the evidence and revise previous recommendations as needed.

Results: The primary literature review included 15 meta-analyses of RCTs and two RCTs. A growing body of evidence suggests that adding iron to treatment with an ESA may improve hematopoietic response and reduce the likelihood of RBC transfusion. The biosimilar literature review suggested that biosimilars of epoetin alfa have similar efficacy and safety to reference products, although evidence in cancer remains limited.

Recommendations: ESAs (including biosimilars) may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin has declined to < 10 g/dL. RBC transfusion is also an option. With the exception of selected patients with myelodysplastic syndromes, ESAs should not be offered to most patients with nonchemotherapy-associated anemia. During ESA treatment, hemoglobin may be increased to the lowest concentration needed to avoid transfusions. Iron replacement may be used to improve hemoglobin response and reduce RBC transfusions for patients receiving ESA with or without iron deficiency. Additional information is available at www.asco.org/supportive-care-guidelines and www.hematology.org/guidelines.
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http://dx.doi.org/10.1182/bloodadvances.2018030387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482353PMC
April 2019

Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update.

J Clin Oncol 2019 05 10;37(15):1336-1351. Epub 2019 Apr 10.

13 Western University, London, Ontario, Canada.

Purpose: To update the American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer.

Methods: PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and meta-analyses of RCTs in patients with cancer published from January 31, 2010, through May 14, 2018. For biosimilar ESAs, the literature search was expanded to include meta-analyses and RCTs in patients with cancer or chronic kidney disease and cohort studies in patients with cancer due to limited RCT evidence in the cancer setting. ASCO and ASH convened an Expert Panel to review the evidence and revise previous recommendations as needed.

Results: The primary literature review included 15 meta-analyses of RCTs and two RCTs. A growing body of evidence suggests that adding iron to treatment with an ESA may improve hematopoietic response and reduce the likelihood of RBC transfusion. The biosimilar literature review suggested that biosimilars of epoetin alfa have similar efficacy and safety to reference products, although evidence in cancer remains limited.

Recommendations: ESAs (including biosimilars) may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin has declined to < 10 g/dL. RBC transfusion is also an option. With the exception of selected patients with myelodysplastic syndromes, ESAs should not be offered to most patients with nonchemotherapy-associated anemia. During ESA treatment, hemoglobin may be increased to the lowest concentration needed to avoid transfusions. Iron replacement may be used to improve hemoglobin response and reduce RBC transfusions for patients receiving ESA with or without iron deficiency. Additional information is available at www.asco.org/supportive-care-guidelines and www.hematology.org/guidelines .
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http://dx.doi.org/10.1200/JCO.18.02142DOI Listing
May 2019

MDS overlap disorders and diagnostic boundaries.

Blood 2019 03 22;133(10):1086-1095. Epub 2019 Jan 22.

Division of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA.

Myelodysplastic syndromes (MDS) are clonal diseases defined by clinical, morphologic, and genetic features often shared by related myeloid disorders. The diagnostic boundaries between these diseases can be arbitrary and not necessarily reflective of underlying disease biology or outcomes. In practice, measures that distinguish MDS from related disorders may be difficult to quantify and can vary as disease progression occurs. Patients may harbor findings that are not consistent with a single diagnostic category. Several overlap disorders have been formally described, such as the myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). These disorders are characterized by hematopoietic dysplasia with increased proliferation of monocytes, neutrophils, or platelets. They may have mutational profiles that distinguish them from the disorders they resemble and reflect important differences in pathophysiology. MDS also shares diagnostic borders with other diseases. For example, aplastic anemia and hypoplastic MDS can be difficult to distinguish in patients with pancytopenia and bone marrow hypocellularity. Genetic features may help in this regard, because they can identify differences in prognosis and risk of progression. The boundary between MDS and secondary acute myeloid leukemia (sAML) is arbitrarily defined and has been redefined over the years. Genetic studies have demonstrated that sAML clones can precede clinical progression from MDS by many months, suggesting that MDS with excess blasts could be viewed as an overlap between a dysplastic bone marrow failure syndrome and an oligoblastic leukemia. This review will describe the diagnostic boundaries between MDS, MDS/MPNs, sAML, clonal hematopoiesis of indeterminate potential, clonal cytopenia of undetermined significance, and aplastic anemia and how genetic approaches may help to better define them.
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http://dx.doi.org/10.1182/blood-2018-10-844670DOI Listing
March 2019

A Phase I/II Trial of the Combination of Azacitidine and Gemtuzumab Ozogamicin for Treatment of Relapsed Acute Myeloid Leukemia.

Clin Lymphoma Myeloma Leuk 2018 05 2;18(5):346-352.e5. Epub 2018 Mar 2.

Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego, Moores Cancer Center, La Jolla, CA. Electronic address:

Introduction: Treatment with hypomethylating agent therapy might enhance anti-CD33 monoclonal antibody-mediated cytotoxicity against acute myeloid leukemia (AML) blasts through epigenetic effects on Syk and SHP-1 expression.

Patients And Methods: In the present phase I/II study, we treated patients with relapsed or refractory AML with azacitidine, followed by 2 doses of gemtuzumab ozogamicin (GO) at 6 mg/m, the Food and Drug Administration-approved dose and schedule at study initiation. We sought to determine the maximum tolerated dose and clinical activity of this combination therapy. Secondarily, we aimed to determine whether baseline Syk and SHP-1 expression can be used as predictive biomarkers of treatment response.

Results: The established maximum tolerated dose was azacitidine 75 mg/m daily for 6 consecutive days, followed by GO 6 mg/m on days 7 and 21. Of the 50 evaluable patients, 12 (24%) obtained complete remission (CR) or CR with incomplete peripheral blood recovery (CRp). No dose-limiting toxicities were observed in phase I, and no patient developed hepatic sinusoidal obstructive syndrome. Although no significant correlation was found between Syk and SHP-1 expression and the clinical response to combination therapy, in vitro studies repeatedly demonstrated that azacitidine-treated AML cells had an increased response to GO treatment.

Conclusion: Our study found that the combination of GO with azacitidine is relatively well tolerated, with response rates similar to those with GO monotherapy at higher doses. Differences in the GO drug schedule, dose level, and frequency might explain the discrepant response rates between our study and others, suggesting that the optimal GO dose remains unclear, especially when combined with hypomethylating agent therapy.
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http://dx.doi.org/10.1016/j.clml.2018.02.017DOI Listing
May 2018

SOHO State of the Art Update and Next Questions: Biology and Treatment of Myelodysplastic Syndromes.

Clin Lymphoma Myeloma Leuk 2017 10 25;17(10):613-620. Epub 2017 Sep 25.

Moores Cancer Center, University of California, San Diego, La Jolla, CA.

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms characterized by clonal hematopoiesis leading to bone marrow dysplasia and cytopenias. Recently, significant advancements have been made in understanding the pathogenic mechanisms of this disease. In particular, how a wide array of somatic mutations can induce a common clinical phenotype has been investigated. Specifically, activation of innate immune signaling (i.e. myeloid derived suppressor cells) and the NLRP3 inflammasome in hematopoietic stem/progenitor cells play a central role in the biology of MDS, leading to pyroptotic cell death and clonal expansion. Additionally, deciphering the molecular drivers of MDS using next-generation sequencing has rapidly expanded our understanding of MDS with profound implications for prognosis, treatment decisions, and future clinical investigations. Together, unraveling of the role of innate immunity/pyroptosis in the clinical phenotype of MDS patients and comprehensive molecular characterization has identified novel therapeutic strategies that offer significant promise.
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http://dx.doi.org/10.1016/j.clml.2017.09.018DOI Listing
October 2017
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