Asiri Saumya Ediriwickrema

All Publications

• Single cell genomics in AML: extending the frontiers of AML research. Blood Ediriwickrema, A., Gentles, A. J., Majeti, R. 2022

  Abstract

  The era of genomic medicine has allowed AML researchers to improve disease characterization, optimize risk stratification systems, and develop new treatments. While there has been significant progress, AML remains a lethal cancer due to its remarkably complex and plastic cellular architecture. This degree of heterogeneity continues to pose a major challenge as it limits the ability to identify and therefore eradicate the cells responsible for leukemogenesis and treatment failures. In recent years, the field of single cell genomics has led to unprecedented strides in the ability to characterize cellular heterogeneity and holds promise for the study of AML. In this review, we will highlight advancements in single cell technologies, outline important shortcomings in our understanding of AML biology and clinical management, and discuss how single cell genomics can not only address these shortcomings, but also provide unique opportunities in basic and translational AML research.

  View details for DOI 10.1182/blood.2021014670

  View details for PubMedID 35926108

• Venetoclax and hypomethylating agent therapy in high risk myelodysplastic syndromes: a retrospective evaluation of a real-world experience. Leukemia & lymphoma Azizi, A. n., Ediriwickrema, A. n., Dutta, R. n., Patel, S. A., Shomali, W. n., Medeiros, B. n., Iberri, D. n., Gotlib, J. n., Mannis, G. n., Greenberg, P. n., Majeti, R. n., Zhang, T. n. 2020: 1–8

  Abstract

  Treatment with hypomethylating agents (HMAs) azacitidine or decitabine is the current standard of care for high risk myelodysplastic syndromes (MDSs) but is associated with low rates of response. The limited number of treatment options for patients with high risk MDS highlights a need for new therapeutic options. Venetoclax is an inhibitor of the BCL-2 protein which, when combined with an HMA, has shown high response rates in unfit and previously untreated acute myeloid leukemia. We performed a retrospective study of high risk MDS patients receiving combination HMA plus venetoclax in order to determine their effectiveness in this context. We show that in our cohort, the combination results in high response rates but is associated with a high frequency of myelosuppression. These data highlight the efficacy of combination HMA plus venetoclax in high risk MDS, warranting further prospective evaluation in clinical trials.

  View details for DOI 10.1080/10428194.2020.1775214

  View details for PubMedID 32543932

• Single-cell mutational profiling enhances the clinical evaluation of AML MRD. Blood advances Ediriwickrema, A. n., Aleshin, A. n., Reiter, J. G., Corces, M. R., Köhnke, T. n., Stafford, M. n., Liedtke, M. n., Medeiros, B. C., Majeti, R. n. 2020; 4 (5): 943–52

  Abstract

  Although most patients with acute myeloid leukemia (AML) achieve clinical remission with induction chemotherapy, relapse rates remain high. Next-generation sequencing enables minimal/measurable residual disease (MRD) detection; however, clinical significance is limited due to difficulty differentiating between pre-leukemic clonal hematopoiesis and frankly malignant clones. Here, we investigated AML MRD using targeted single-cell sequencing (SCS) at diagnosis, remission, and relapse (n = 10 relapsed, n = 4 nonrelapsed), with a total of 310 737 single cells sequenced. Sequence variants were identified in 80% and 75% of remission samples for patients with and without relapse, respectively. Pre-leukemic clonal hematopoiesis clones were detected in both cohorts, and clones with multiple cooccurring mutations were observed in 50% and 0% of samples. Similar clonal richness was observed at diagnosis in both cohorts; however, decreasing clonal diversity at remission was significantly associated with longer relapse-free survival. These results show the power of SCS in investigating AML MRD and clonal evolution.

  View details for DOI 10.1182/bloodadvances.2019001181

  View details for PubMedID 32150611

• A sunblock based on bioadhesive nanoparticles NATURE MATERIALS Deng, Y., Ediriwickrema, A., Yang, F., Lewis, J., Girardi, M., Saltzman, W. M. 2015; 14 (12): 1278-1285

  Abstract

  The majority of commercial sunblock preparations use organic or inorganic ultraviolet (UV) filters. Despite protecting against cutaneous phototoxicity, direct cellular exposure to UV filters has raised a variety of health concerns. Here, we show that the encapsulation of padimate O (PO)--a model UV filter--in bioadhesive nanoparticles (BNPs) prevents epidermal cellular exposure to UV filters while enhancing UV protection. BNPs are readily suspended in water, facilitate adherence to the stratum corneum without subsequent intra-epidermal or follicular penetration, and their interaction with skin is water resistant yet the particles can be removed via active towel drying. Although the sunblock based on BNPs contained less than 5 wt% of the UV-filter concentration found in commercial standards, the anti-UV effect was comparable when tested in two murine models. Moreover, the BNP-based sunblock significantly reduced double-stranded DNA breaks when compared with a commercial sunscreen formulation.

  View details for DOI 10.1038/NMAT4422

  View details for PubMedID 26413985

• Nanotherapy for Cancer: Targeting and Multifunctionality in the Future of Cancer Therapies ACS BIOMATERIALS SCIENCE & ENGINEERING Ediriwickrema, A., Saltzman, W. M. 2015; 1 (2): 64-78

  Abstract

  Cancer continues to be a prevalent and lethal disease, despite advances in tumor biology research and chemotherapy development. Major obstacles in cancer treatment arise from tumor heterogeneity, drug resistance, and systemic toxicities. Nanoscale delivery systems, or nanotherapies, are increasing in importance as vehicles for antineoplastic agents because of their potential for targeting and multifunctionality. We discuss the current field of cancer therapy and potential strategies for addressing obstacles in cancer treatment with nanotherapies. Specifically, we review the strategies for rationally designing nanoparticles for targeted, multimodal delivery of therapeutic agents.

  View details for DOI 10.1021/ab500084g

  View details for PubMedID 25984571

• Multi-layered nanoparticles for combination gene and drug delivery to tumors BIOMATERIALS Ediriwickrema, A., Zhou, J., Deng, Y., Saltzman, W. M. 2014; 35 (34): 9343-9354

  Abstract

  Drug resistance and toxicity are major obstacles in cancer chemotherapy. Combination therapies can overcome resistance, and synergies can minimize dosing. Polymer nanocarriers are interesting vehicles for cancer therapeutics for their delivery and tumor targeting abilities. We synthesized a multi-layered polymer nanoparticle (MLNP), comprising of poly(lactic-co-glycolic acid) with surface polyethyleneimine and functional peptides, for targeted drug and gene delivery. We confirmed the particle's ability to inhibit tumor growth through synergistic action of the drug and gene product. MLNPs achieved transfection levels similar to lipofectamine, while maintaining minimal cytotoxicity. The particles delivered camptothecin (CPT), and plasmid encoding TNF related apoptosis inducing ligand (pTRAIL) (CT MLNPs), and synergistically inhibited growth of multiple cancer cells in vitro. The synergy of co-delivering CPT and pTRAIL via CT MLNPs was confirmed using the Chou-Talalay method: the combination index (CI) values at 50% inhibition ranged between 0.31 and 0.53 for all cell lines. Further, co-delivery with MLNPs resulted in a 3.1-15 fold reduction in CPT and 4.7-8.0 fold reduction in pTRAIL dosing. CT MLNPs obtained significant HCT116 growth inhibition in vivo compared to monotherapy. These results support our hypothesis that MLNPs can deliver both small molecules and genetic agents towards synergistically inhibiting tumor growth.

  View details for DOI 10.1016/j.biomaterials.2014.07.043

  View details for PubMedID 25112935

• Simplified Intrafemoral Injections Using Live Mice Allow for Continuous Bone Marrow Analysis. Journal of visualized experiments : JoVE Nakauchi, Y., Ediriwickrema, A., Martinez-Krams, D., Zhao, F., Rangavajhula, A., Karigane, D., Majeti, R. 2023

  Abstract

  Despite the complexity of hematopoietic cell transplantation in humans, researchers commonly perform intravenous or intrafemoral (IF) injections in mice. In murine models, this technique has been adapted to enhance the seeding efficiency of transplanted hematopoietic stem and progenitor cells (HSPCs). This paper describes a detailed step-by-step technical procedure of IF injection and the following bone marrow (BM) aspiration in mice that allows for serial characterization of cells present in the BM. This method enables the transplantation of valuable samples with low cell numbers that are particularly difficult to engraft by intravenous injection. This procedure facilitates the creation of xenografts that are critical for pathological analysis. While it is easier to access peripheral blood (PB), the cellular composition of PB does not reflect the BM, which is the niche for HSPCs. Therefore, procedures providing access to the BM compartment are essential for studying hematopoiesis. IF injection and serial BM aspiration, as described here, allow for the prospective retrieval and characterization of cells enriched in the BM, such as HSPCs, without sacrificing the mice.

  View details for DOI 10.3791/65874

  View details for PubMedID 38009738

• Prognostic heterogeneity and clonal dynamics within distinct subgroups of myelodysplastic syndrome and acute myeloid leukemia with TP53 disruptions. EJHaem Patel, S. A., Cerny, J., Gerber, W. K., Ramanathan, M., Ediriwickrema, A., Tanenbaum, B., Hutchinson, L., Meng, X., Flahive, J., Barton, B., Gillis-Smith, A. J., Suzuki, S., Khedr, S., Selove, W., Higgins, A. W., Miron, P. M., Simin, K., Woda, B., Gerber, J. M. 2023; 4 (4): 1059-1070

  Abstract

  TP53 aberrations constitute the highest risk subset of myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). The International Consensus Classification questions the blast threshold between MDS and AML. In this study, we assess the distinction between MDS and AML for 76 patients with TP53 aberrations. We observed no significant differences between MDS and AML regarding TP53 genomics. Median overall survival (OS) was 223 days for the entire group, but prognostic discrimination within subgroups showed the most inferior OS (46 days) for AML with multihit allelic state plus TP53 variant allele frequency (VAF) > 50%. In multivariate analysis, unadjusted Cox models revealed the following variables as independent risk factors for mortality: AML (vs. MDS) (hazard ratio [HR]: 2.50, confidence interval [CI]: 1.4-4.4, p = 0.001), complex karyotype (HR: 3.00, CI: 1.4-6.1, p = 0.003), multihit status (HR: 2.30, CI 1.3-4.2, p = 0.005), and absence of hematopoietic cell transplant (HCT) (HR: 3.90, CI: 1.8-8.9, p = 0.0009). Clonal dynamic modeling showed a significant reduction in TP53 VAF with front-line hypomethylating agents. These findings clarify the impact of specific covariates on outcomes of TP53-aberrant myeloid neoplasms, irrespective of the diagnosis of MDS versus AML, and may influence HCT decisions.

  View details for DOI 10.1002/jha2.791

  View details for PubMedID 38024632

  View details for PubMedCentralID PMC10660125

• Peripheral blood DNA methylation profiles predict future development of B-cell Non-Hodgkin Lymphoma. NPJ precision oncology Espin-Perez, A., Brennan, K., Ediriwickrema, A. S., Gevaert, O., Lossos, I. S., Gentles, A. J. 2022; 6 (1): 53

  Abstract

  Lack of accurate methods for early lymphoma detection limits the ability to cure patients. Since patients with Non-Hodgkin lymphomas (NHL) who present with advanced disease have worse outcomes, accurate and sensitive methods for early detection are needed to improve patient care. We developed a DNA methylation-based prediction tool for NHL, based on blood samples collected prospectively from 278 apparently healthy patients who were followed for up to 16 years to monitor for NHL development. A predictive score was developed using machine learning methods in a robust training/validation framework. Our predictive score incorporates CpG DNA methylation at 135 genomic positions, with higher scores predicting higher risk. It was 85% and 78% accurate for identifying patients at risk of developing future NHL, in patients with high or low epigenetic mitotic clock respectively, in a validation cohort. It was also sensitive at detecting active NHL (96.3% accuracy) and healthy status (95.6% accuracy) in additional independent cohorts. Scores optimized for specific NHL subtypes showed significant but lower accuracy for predicting other subtypes. Our score incorporates hyper-methylation of Polycomb and HOX genes, which have roles in NHL development, as well as PAX5 - a master transcriptional regulator of B-cell fate. Subjects with higher risk scores showed higher regulatory T-cells, memory B-cells, but lower naive T helper lymphocytes fractions in the blood. Future prospective studies will be required to confirm the utility of our signature for managing patients who are at high risk for developing future NHL.

  View details for DOI 10.1038/s41698-022-00295-3

  View details for PubMedID 35864305

• The cell type specific 5hmC landscape and dynamics of healthy human hematopoiesis and TET2-mutant pre-leukemia. Blood cancer discovery Nakauchi, Y., Azizi, A., Thomas, D., Corces, M. R., Reinisch, A., Sharma, R., Cruz Hernandez, D., Kohnke, T., Karigane, D., Fan, A., Martinez-Krams, D., Stafford, M., Kaur, S., Dutta, R., Phan, P., Ediriwickrema, A., McCarthy, E., Ning, Y., Phillips, T., Ellison, C. K., Guler, G. D., Bergamaschi, A., Ku, C., Levy, S., Majeti, R. 2022

  Abstract

  The conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is a key step in DNA demethylation that is mediated by ten-eleven-translocation (TET) enzymes, which require ascorbate/vitamin C. Here, we report the 5hmC landscape of normal hematopoiesis and identify cell type-specific 5hmC profiles associated with active transcription and chromatin accessibility of key hematopoietic regulators. We utilized CRISPR/Cas9 to model TET2 loss-of-function mutations in primary human HSPCs. Disrupted cells exhibited increased colonies in serial replating, defective erythroid/megakaryocytic differentiation, and in vivo competitive advantage and myeloid skewing coupled with reduction of 5hmC at erythroid-associated gene loci. Azacitidine and ascorbate restored 5hmC abundance and slowed or reverted the expansion of TET2-mutant clones in vivo. These results demonstrate the key role of 5hmC in normal hematopoiesis and TET2-mutant phenotypes and raise the possibility of utilizing these agents to further our understanding of pre-leukemia/clonal hematopoiesis.

  View details for DOI 10.1158/2643-3230.BCD-21-0143

  View details for PubMedID 35532363

• Modeling the Development of SRSF2 Mutated Myeloid Malignancies By CRISPR/Cas9 Mediated Genome Engineering of Primary Human Hematopoietic Stem and Progenitor Cells Pabst, G., Fosselteder, J., Schlacher, A., Auinger, L., Martinez-Krams, D., Ediriwickrema, A., Kashofer, K., Beham-Schmid, C., Greinix, H. T., Woelfler, A., Schlenke, P., Sill, H., Zebisch, A., Majeti, R., Reinisc, A. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-149591

  View details for Web of Science ID 000736413900158

• Single Cell Analysis of Adult Human Hematopoietic Stem and Progenitor Cells Identifies a Novel Lymphoid Primed Multipotent Progenitor That Expands in Relapsed Acute Myeloid Leukemia Ediriwickrema, A., Luca, B. A., Newman, A. M., Gentles, A. J., Majeti, R. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-148993

  View details for Web of Science ID 000736413905078

• Chromatin Accessibility Analysis Reveals Epigenetic Evolution Is a Common Mechanism of Relapse in Acute Myeloid Leukemia Nuno, K. A., Azizi, A., Koehnke, T., Ediriwickrema, A., Corces, M., Majeti, R. 2021

  View details for DOI 10.1182/blood-2021-148928

• Clinico-genomic profiling and clonal dynamic modeling of TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia. Leukemia & lymphoma Patel, S. A., Lloyd, M. R., Cerny, J., Shi, Q., Simin, K., Ediriwickrema, A., Hutchinson, L., Miron, P. M., Higgins, A. W., Ramanathan, M., Gerber, J. M. 2021: 1-13

  Abstract

  TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia have dismal outcomes. Here, we define the clinico-genomic landscape of TP53 disruptions in 40 patients and employ clonal dynamic modeling to map the mutational hierarchy against clinical outcomes. Most TP53 mutations (45.2%) localized to the L3 loop or LSH motif of the DNA-binding domain. TP53 disruptions had high co-occurrence with mutations in epigenetic regulators, spliceosome machinery, and cohesin complex and low co-occurrence with mutations in proliferative signaling genes. Ancestral and descendant TP53 mutations constituted measurable residual disease and fueled relapse. High mutant TP53 gene dosage predicted low durability of remission. The median overall survival (OS) was 280 days. Hypomethylating agent-based therapy served as an effective bridge to transplant, leading to improved median OS compared to patients who did not receive a transplant (14.7 vs. 5.1 months). OS was independent of the genomic location of TP53 disruption, which has implications for rational therapeutic design.

  View details for DOI 10.1080/10428194.2021.1957869

  View details for PubMedID 34496723

• Successful treatment of thrombocytopenia with daratumumab after allogeneic transplant: a case report and literature review. Blood advances Migdady, Y., Ediriwickrema, A., Jackson, R. P., Kadi, W., Gupta, R., Socola, F., Arai, S., Martin, B. A. 2020; 4 (5): 815–18

  View details for DOI 10.1182/bloodadvances.2019001215

  View details for PubMedID 32119735

• Multiomic single cell analysis of normal human bone marrow identifies a unique stem and progenitor population that expands in AML Proceedings of the Annual Meeting of the American Association for Cancer Research 2020 Ediriwickrema, A., Ramakrishnan, S., Nakamoto, M., Ghanekar, S., Luca, B., Newman, A., Gentles, A., Majeti, R. 2020

  View details for DOI 10.1158/1538-7445.AM2020-3779

• Granulocyte Transfusions in a Cohort of Neutropenic Patients with Life-Threatening Infections and Hematologic Diseases AMER SOC HEMATOLOGY Ediriwickrema, A., Virk, M., Andrews, J. 2019: 3696

  View details for DOI 10.1182/blood-2019-127103

• A Case Report of Refractory Immune Thrombocytopenia (ITP) Following Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Myelodysplastic Syndrome (MDS) Successfully Treated with Off-Label Use of Daratumumab Migdady, Y., Gupta, R., Ediriwickrema, A., Socola, F., Arai, S., Martin, B. A. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-116560

  View details for Web of Science ID 000454842805252

• Comprehensive Cytokine Profiling of Patients with Advanced Systemic Mastocytosis Treated with Midostaurin Ediriwickrema, A., DeAngelo, D. J., George, T. I., Rosenberg-Hasson, Y., Perkins, C., Langford, C., Gotlib, J. R. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-117689

  View details for Web of Science ID 000454837605151

• Crescentic Glomerulonephritis With Immunoglobulin G4-Related Disease. The American journal of the medical sciences Raber, I. n., Ediriwickrema, A. n., Higgins, J. n., Kambham, N. n., Pao, A. C. 2017; 354 (3): 236–39

  Abstract

  Immunoglobulin G4 (IgG4)-related disease is an uncommon autoimmune disease that affects multiple organ systems. Renal involvement typically presents as tubulointerstitial nephritis and less commonly as membranous glomerulonephritis. In this case report, we discuss a 68-year-old patient who presented with rapidly progressive glomerulonephritis. His renal biopsy revealed a membranoproliferative pattern of injury with fibrocellular crescents and extensive infiltration of the tubulointerstitium with IgG4-positive plasma cells. We treated the patient with both corticosteroids and rituximab because of the aggressive nature of crescentic glomerulonephritis. The patient demonstrated a partial improvement in kidney function after 2 cycles of rituximab with a decrease in serum creatinine levels from 6.9-4.7mg/dL after 6 months from presentation. This case illustrates the importance of considering IgG4-related disease in cases of rapidly progressive glomerulonephritis and the need for effective treatments for more aggressive forms of this recently recognized disease entity.

  View details for PubMedID 28918828

• Acute bitemporal hemianopsia from a compressive anterior communicating artery aneurysm NEUROLOGY AND CLINICAL NEUROSCIENCE Keung, B., Ediriwickrema, A., Bulsara, K. 2015; 3 (3): 114–15

  View details for DOI 10.1111/ncn3.146

  View details for Web of Science ID 000218759400008

• Tissue plasminogen activator via cross-collateralization for tandem internal carotid and middle cerebral artery occlusion. World journal of clinical cases Bulsara, K. R., Ediriwickrema, A., Pepper, J., Robertson, F., Aruny, J., Schindler, J. 2013; 1 (9): 290-294

  Abstract

  Tandem internal carotid and middle cerebral artery occlusion after carotid dissection predicts poor outcome after systemic thrombolysis. Current treatments include the use of endovascular carotid stenting, which carries with it a high risk of propagating further embolic events and worsening the dissection. New strategies for avoiding the aforementioned side-effects include recanalization using cross-collaterals for delivery of intra-lesional tissue plasminogen activator (tPA). We present two cases that provide further support for this novel approach. Both patients presented with a National Institute of Health Stroke Scale of 20, received intra-arterial tPA via cross-collateralization, and made full recoveries without the need for stenting.

  View details for DOI 10.12998/wjcc.v1.i9.290

  View details for PubMedID 24364024

  View details for PubMedCentralID PMC3868713

• Flow diverters and a tale of two aneurysms. Journal of neurointerventional surgery Kuzmik, G. A., Williamson, T., Ediriwickrema, A., Andeejani, A., Bulsara, K. R. 2013; 5 (4)

  Abstract

  Flow-diverting devices offer an exciting alternative for the management of large and giant intracranial aneurysms. However, the risk and mechanism of delayed aneurysmal rupture and hemorrhage following placement of these devices are not clearly understood. Two patients with similar symptomatic giant paraclinoid internal carotid artery aneurysms are described. Both patients were treated with SILK flow-diverting devices. In both patients the SILK device was placed without technical complication. The first patient continued to do well 1 year postoperatively with complete aneurysm occlusion. The second patient had a delayed subarachnoid hemorrhage despite markedly decreased filling of the aneurysm immediately following the procedure. Flow-diverting devices are an exciting technology which provide an alternative treatment modality in the management of giant intracranial aneurysms. However, caution must be exercised as the risks of delayed complications have yet to be fully elucidated. Similar aneurysms may have drastically different outcomes due to the unpredictability of this technology.

  View details for DOI 10.1136/neurintsurg-2012-010316

  View details for PubMedID 22510458

• Intracranial stenting as monotherapy in subarachnoid hemorrhage and sickle cell disease. Journal of neurointerventional surgery Ediriwickrema, A., Williamson, T., Hebert, R., Matouk, C., Johnson, M. H., Bulsara, K. R. 2013; 5 (2)

  Abstract

  Although there have been a few reports of coiling intracranial aneurysms in patients with sickle cell disease (SCD), there are no reports of intracranial stent placement in this patient population. A patient in whom stent placement was utilized as monotherapy to treat a blister-like aneurysm is described and the implications of SCD and endovascular treatment are discussed.A 37-year-old man with SCD presented with diffuse subarachnoid hemorrhage. Angiography confirmed a 2 mm irregular aneurysm on the posterior cerebral artery which was treated with an oversized Neuroform 3 stent that was placed across the aneurysm neck by the senior author (KRB). Follow-up CT angiography showed no residual aneurysmal filling. The patient was discharged home in a stable condition, and he continues to do well 4 weeks following the procedure with no recurrence of the aneurysm.This report reviews hypercoagulability in SCD and the treatment options for intracranial aneurysms in patients with SCD. Additionally, the reported case suggests that intracranial stent placement may be a viable option for treating complex intracranial aneurysms in SCD patients.

  View details for DOI 10.1136/neurintsurg-2011-010224

  View details for PubMedID 22248629