Overview

The goal of the Porter lab is to develop novel therapeutic strategies for leukemia through better understanding of molecular mechanisms of leukemogenesis and treatment resistance. We employ a wide variety of techniques, in vitro and in vivo, for discovery and validation of molecular vulnerabilities in cancer cells.

A major focus of the lab is directed at understanding mechanisms of immune evasion during leukemogenesis, as well as enhancing immune cells’ response to leukemia cells. Specifically, we are studying the role of a newly describe immune checkpoint protein, Siglec15, in leukemia and lymphoma.

The Role of ETV6 in B Lymphopoiesis and Leukemogenesis

Consistent with our clinical interest in Cancer Predisposition Syndromes, and in collaboration with colleagues locally and internationally, we identified a novel syndrome in which affected family members have thrombocytopenia and predisposition to develop acute lymphoblastic leukemia due to germline mutations in ETV6 (Noetzli et al, Nat Genet, 2015). While rearrangements and mutations in ETV6 are common in acute lymphoblastic leukemia (ALL), we were among the first to define this new leukemia predisposition syndrome. This work underscores the value of screening the genome in kindreds with cancer to identify novel cancer predisposition mutations that may lead to better mechanistic understanding of oncogenesis. Indeed, new experiments are revealing a novel mechanistic role for ETV6 in hematopoiesis.

Mechanisms of Immune Evasion During Leukemogenesis

While evasion of the immune system is considered one of the defining features of cancer, the mechanisms by which leukemia cells evade immune detection and elimination remain incompletely understood. We have found that leukemia-cell calcineurin is required for immune evasion in a mouse model of leukemia (Rabe et al, Cancer Res, 2019). This work identified IL-12 as a potent stimulator of T cell response to leukemia cells, which we are now trying to exploit as a therapeutic strategy in collaboration with Erik Dreaden, PhD. In addition, we have discovered that Siglec15 is a novel immunomodulatory molecule, which can be inhibited to promote T cell killing of leukemia cells.

Single Cell Transcriptomics

The presence of minimal residual disease (MRD) is one of the most reliable risk factors for relapse in both ALL and AML and has become a routine part of clinical decision making – when present, intensified therapy is indicated. As part of the Aflac Precision Medicine Program Leukemia/Lymphoma Research Team, our lab has approached this phenomenon to study mechanisms of treatment failure with several strategies. One of these strategies includes the use of single-cell mRNA-sequencing (scRNA-seq) to study leukemia cells and non-leukemia cells sorted from children with B cell acute lymphoblastic leukemia, with or without MRD at the end of induction. This includes ongoing collaborations with Gregory Gibson, PhD and Manoj Bhasin, PhD, in projects on ALL and AML, respectively.

Jodi Dougan, Lead Research Specialist

jodi.dougan@emory.edu


Miyoung Lee, PhD, Instructor of Pediatrics 

miyoung.lee@emory.edu


Dailia Francis, MD, PhD, Instructor of Pediatrics 

dailia.benita.francis@emory.edu


Mercy Coleman 

mercy.coleman@emoryhealthcare.org

Chengjing Zhou, MD, Senior Research Specialist

Rizvan Uluisik, PhD, Postdoctoral Fellow

Camille David, Lead Research Specialist

Rae Hunter, PhD Candidate 

Claire Pillsbury, PhD Candidate 

Mumme H, Thomas BE, Bhasin SS, Krishnan U, Dwivedi B, Perumalla P, Sarkar D, Ulukaya GB, Sabnis HS, Park SI, DeRyckere D, Raikar SS, Pauly M, Summers RJ, Castellino SM, Wechsler DS, Porter CC, Graham DK, Bhasin M. Single-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia. Nat Commun. 2023 Oct 5;14(1):6209. doi: 10.1038/s41467-023-41994-0. PMID: 37798266; PMCID: PMC10556066.

Pillsbury CE, Dougan J, Rabe JL, Fonseca JA, Zhou C, Evans AN, Abukharma H, Ichoku O, Gonzalez-Flamenco G, Park SI, Aljudi A, DeRyckere D, Castellino SM, Rafiq S, Langermann S, Liu LN, Henry CJ, Porter CC. Siglec-15 Promotes Evasion of Adaptive Immunity in B-cell Acute Lymphoblastic Leukemia. Cancer Res Commun. 2023 Jul 17;3(7):1248-1259. doi: 10.1158/2767-9764.CRC-23-0056. PMID: 37465593; PMCID: PMC10351425.

Hunter R, Imbach KJ, Zhou C, Dougan J, Hamilton JAG, Chen KZ, Do P, Townsel A, Gibson G, Dreaden EC, Waller EK, Haynes KA, Henry CJ, Porter CC. B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12. Sci Rep. 2022 Jul 13;12(1):11870. doi: 10.1038/s41598-022-16152-z. PMID: 35831470; PMCID: PMC9279427.

Zhou C, Uluisik R, Rowley JW, David C, Jones CL, Scharer CD, Noetzli L, Fisher MH, Kirkpatrick GD, Bark K, Boss JM, Henry CJ, Pietras EM, Di Paola J, Porter CC. Germline ETV6 mutation promotes inflammation and disrupts lymphoid development of early hematopoietic progenitors. Exp Hematol. 2022 Aug-Sep;112-113:24-34. doi: 10.1016/j.exphem.2022.06.002. Epub 2022 Jul 6. PMID: 35803545; PMCID: PMC9885892.

Summers RJ, Castellino SM, Porter CC, MacDonald TJ, Basu GD, Szelinger S, Bhasin MK, Cash T, Carter AB, Castellino RC, Fangusaro JR, Mitchell SG, Pauly MG, Pencheva B, Wechsler DS, Graham DK, Goldsmith KC. Comprehensive Genomic Profiling of High-Risk Pediatric Cancer Patients Has a Measurable Impact on Clinical Care. JCO Precis Oncol. 2022 Apr;6:e2100451. doi: 10.1200/PO.21.00451. PMID: 35544730.

Lee M, Hamilton JAG, Talekar GR, Ross AJ, Michael L, Rupji M, Dwivedi B, Raikar SS, Boss J, Scharer CD, Graham DK, DeRyckere D, Porter CC, Henry CJ. Obesity-induced galectin-9 is a therapeutic target in B-cell acute lymphoblastic leukemia. Nat Commun. 2022 Mar 3;13(1):1157. doi: 10.1038/s41467-022-28839-y. PMID: 35241678; PMCID: PMC8894417.

Do P, Perdue LA, Chyong A, Hunter R, Dougan J, Henry CJ, Porter CC, Dreaden EC. Rapid Assembly and Screening of Multivalent Immune Cell-Redirecting Therapies for Leukemia. ACS Comb Sci. 2020 Oct 12;22(10):533-541. doi: 10.1021/acscombsci.0c00081. Epub 2020 Aug 18. PMID: 32786324; PMCID: PMC8496977.
 

 

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CURE Childhood Cancer – 07/2017-06/2023

Aflac Precision Medicine Program 

Role: Co-Leader

 

St. Baldrick’s Foundation – 07/2019-06/2025

Consortium for Childhood Cancer Research

Role: Co-PI

 

Translational Research Project, Leukemia & Lymphoma Society – 07/2022-06/2025

Targeting Siglec15 to promote immune response to malignant B cells

Role: PI

 

Hyundai Hope on Wheels Foundation - Hope Scholar Award - 01/2023-12/2024

Immune therapy for pediatric hematologic malignancies targeting Siglec15

Role: PI