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. For example, using a genome-scale shRNA screen, we identified WEE1 as a chemosensitizing target in acute myeloid leukemia (AML) cells. Subsequent studies funded by the NCI have validated this finding and supported the development of a clinical trials a WEE1 inhibitor in subjects with AML. More recently, we have discovered a novel function for the transcription factor ETV6 in regulating normal hematopoiesis and are testing whether and how Etv6 mutation promotes leukemogenesis using a new mouse model with a point mutation in Etv6. Another project in the lab is directed at understanding mechanisms of immune evasion during leukemogenesis, as well as enhancing immune cells’ response to leukemia cells.
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.
Chengjing Zhou, MD, Senior Research Specialist
Rizvan Uluisik, PhD, Postdoctoral Fellow
Jodi Dougan, Lead Research Specialist
Camille David, Lead Research Specialist
Rae Hunter, PhD Candidate (Cancer Biology)
Claire Pillsbury, PhD Candidate (Cancer Biology)
Perdue LA, Do P, David C, Chyong A, Kellner A, Ruggieri A, Kim HR, Salaita K, Lesinski GB, Porter CC, Dreaden EC. Optical Control of Cytokine Signaling via Bioinspired, Polymer-Induced Latency. Biomacromolecules. 2020 May 6. doi: 10.1021/acs.biomac.0c00264. [Epub ahead of print] PubMed PMID: 32374589.
Garcia TB, Uluisik RC, van Linden AA, Jones KL, Venkataraman S, Vibhakar R, Porter CC. Increased HDAC Activity and c-MYC Expression Mediate Acquired Resistance to WEE1 Inhibition in Acute Leukemia. Front Oncol. 2020 Mar 5;10:296. doi: 10.3389/fonc.2020.00296. eCollection 2020. PubMed PMID: 32195191; PubMed Central PMCID: PMC7066074.
Waugh KA, Araya P, Pandey A, Jordan KR, Smith KP, Granrath RE, Khanal S, Butcher ET, Estrada BE, Rachubinski AL, McWilliams JA, Minter R, Dimasi T, Colvin KL, Baturin D, Pham AT, Galbraith MD, Bartsch KW, Yeager ME, Porter CC, Sullivan KD, Hsieh EW, Espinosa JM. Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome. Cell Rep. 2019 Nov 12;29(7):1893-1908.e4. doi: 10.1016/j.celrep.2019.10.038. PubMed PMID: 31722205; PubMed Central PMCID: PMC6871766.
Luo X, Feurstein S, Mohan S, Porter CC, Jackson SA, Keel S, Chicka M, Brown AL, Kesserwan C, Agarwal A, Luo M, Li Z, Ross JE, Baliakas P, Pineda-Alvarez D, DiNardo CD, Bertuch AA, Mehta N, Vulliamy T, Wang Y, Nichols KE, Malcovati L, Walsh MF, Rawlings LH, McWeeney SK, Soulier J, Raimbault A, Routbort MJ, Zhang L, Ryan G, Speck NA, Plon SE, Wu D, Godley LA. ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants. Blood Adv. 2019 Oct 22;3(20):2962-2979. doi: 10.1182/bloodadvances.2019000644. PubMed PMID: 31648317; PubMed Central PMCID: PMC6849945.
Di Paola J, Porter CC. ETV6-related thrombocytopenia and leukemia predisposition. Blood. 2019 Aug 22;134(8):663-667. doi: 10.1182/blood.2019852418. Epub 2019 Jun 27. PubMed PMID: 31248877; PubMed Central PMCID: PMC6706811.
Hamilton KV, Maese L, Marron JM, Pulsipher MA, Porter CC, Nichols KE. Stopping Leukemia in Its Tracks: Should Preemptive Hematopoietic Stem-Cell Transplantation be Offered to Patients at Increased Genetic Risk for Acute Myeloid Leukemia? J Clin Oncol. 2019 Aug 20;37(24):2098-2104. doi: 10.1200/JCO.19.00181. Epub 2019 Jun 6. PubMed PMID: 31170028.
Rabe JL, Gardner L, Hunter R, Fonseca JA, Dougan J, Gearheart CM, Leibowitz MS, Lee-Miller C, Baturin D, Fosmire SP, Zelasko SE, Jones CL, Slansky JE, Rupji M, Dwivedi B, Henry CJ, Porter CC. IL12 Abrogates Calcineurin-Dependent Immune Evasion during Leukemia Progression. Cancer Res. 2019 Jul 15;79(14):3702-3713. doi: 10.1158/0008-5472.CAN-18-3800. Epub 2019 May 29. PubMed PMID: 31142509; PubMed Central PMCID: PMC6889000.
Hart MR, Anderson DJ, Porter CC, Neff T, Levin M, Horwitz MS. Activating PAX gene family paralogs to complement PAX5 leukemia driver mutations. PLoS Genet. 2018 Sep 14;14(9):e1007642. doi: 10.1371/journal.pgen.1007642. eCollection 2018 Sep. PubMed PMID: 30216339; PubMed Central PMCID: PMC6157899.
Cakmakli HF, Torres RJ, Menendez A, Yalcin-Cakmakli G, Porter CC, Puig JG, Jinnah HA. Macrocytic anemia in Lesch-Nyhan disease and its variants. Genet Med. 2019 Feb;21(2):353-360. doi: 10.1038/s41436-018-0053-1. Epub 2018 Jun 6. Review. PubMed PMID: 29875418; PubMed Central PMCID: PMC6281870.
Porter CC, Druley TE, Erez A, Kuiper RP, Onel K, Schiffman JD, Wolfe Schneider K, Scollon SR, Scott HS, Strong LC, Walsh MF, Nichols KE. Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions. Clin Cancer Res. 2017 Jun 1;23(11):e14-e22. doi: 10.1158/1078-0432.CCR-17-0428. Review. PubMed PMID: 28572263.
Ford JB, Baturin D, Burleson TM, Van Linden AA, Kim YM, Porter CC. AZD1775 sensitizes T cell acute lymphoblastic leukemia cells to cytarabine by promoting apoptosis over DNA repair. Oncotarget. 2015 Sep 29;6(29):28001-10. doi: 10.18632/oncotarget.4830. PubMed PMID: 26334102; PubMed Central PMCID: PMC4695040.
Jones CL, Gearheart CM, Fosmire S, Delgado-Martin C, Evensen NA, Bride K, Waanders AJ, Pais F, Wang J, Bhatla T, Bitterman DS, de Rijk SR, Bourgeois W, Dandekar S, Park E, Burleson TM, Madhusoodhan PP, Teachey DT, Raetz EA, Hermiston ML, Müschen M, Loh ML, Hunger SP, Zhang J, Garabedian MJ, Porter CC, Carroll WL. MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia. Blood. 2015 Nov 5;126(19):2202-12. doi: 10.1182/blood-2015-04-639138. Epub 2015 Aug 31. PubMed PMID: 26324703; PubMed Central PMCID: PMC4635116.
Noetzli L, Lo RW, Lee-Sherick AB, Callaghan M, Noris P, Savoia A, Rajpurkar M, Jones K, Gowan K, Balduini C, Pecci A, Gnan C, De Rocco D, Doubek M, Li L, Lu L, Leung R, Landolt-Marticorena C, Hunger S, Heller P, Gutierrez-Hartmann A, Xiayuan L, Pluthero FG, Rowley JW, Weyrich AS, Kahr WHA, Porter CC, Di Paola J. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet. 2015 May;47(5):535-538. doi: 10.1038/ng.3253. Epub 2015 Mar 25. PubMed PMID: 25807284; PubMed Central PMCID: PMC4631613.
Department of Defense, CDMRP (CA180783) – 07/2019-06/2021
Development of bi-specific, T cell engaging cytokine loaded nanoparticles (BiTEokines) for the treatment of childhood cancers
Private Foundation Funded:
CURE Childhood Cancer – 7/1/2017-6/30/2022
Aflac Precision Medicine Program
St. Baldrick’s Foundation – 07/2019-06/2020
Consortium for Childhood Cancer Research
CURE Childhood Cancer – 7/2019-06/2020
Targeting Siglec15 for the treatment of childhood cancers
Alex’s Lemonade Stand Foundation Innovation Award – 10/2019-9/2021
Targeting mechanisms of Siglec15-mediated immune evasion in hematologic malignancies