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In this review, we describe advances in single-cell epigenomics to study cancer biology and how improved approaches can be used to address challenging questions in the field.

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Here we use single-cell ATAC-sequencing to profile heterogeneous cell states that arise in murine primary lung tumors over cancer evolution. These cell states are reproducible and we use computational and functional strategies to identify candidate transcription factor regulators.

Shiny app link to lung tumor atlas

Full List of Publications

LaFave LM^, Savage RE, Buenrostro JD^. Single-Cell Epigenomics Reveals Mechanisms of Cancer Progression. Annual Rev Cancer Bio. 2022 Apr 6:167-185.

^Co-corresponding authors

Concepcion CP, Ma S**, LaFave LM**, Bhutkar A**, Liu M, DeAngelo LP, Kim JY, Del Priore I, Schoenfeld AJ, Miller M, Kartha VK, Westcott PMK, Sanchez-Rivera FJ, Meli K, Gupta M, Bronson RT, Riely GJ, Rekhtman N, Rudin CM, Kim CF, Regev A, Buenrostro JD, Jacks T. SMARCA4 inactivation promotes lineage-specific transformation and early metastatic features in the lung. Cancer Discov. 2021 Sep 24:candisc.0248.2021. doi: 10.1158/2159-8290.CD-21-0248. Epub ahead of print. PMID: 34561242.

**Equal contribution

Del Priore I*, Ma S*, Strecker J, Jacks T, LaFave LM^, Buenrostro JD^. Protocol for single-cell ATAC sequencing using combinatorial indexing in mouse lung adenocarcinoma. STAR Protoc. 2021 Jun 18;2(2):100583. doi: 10.1016/j.xpro.2021.100583. eCollection 2021 Jun 18. PubMed PMID: 34142101; PubMed Central PMCID: PMC8185305.

*Co-first; ^Co-corresponding authors

LaFave LM^, Buenrostro JD^. Unlocking PDAC initiation with AP-1. Nat Cancer. 2021 Jan 13; 2:14-15. doi:10.1038/s43018-020-00158-5

^Co-corresponding authors

Ma S, Zhang B, LaFave LM, Earl AS, Chiang Z, Hu Y, Ding J, Brack A, Kartha VK, Tay T, Law T, Lareau C, Hsu YC, Regev A, Buenrostro JD. Chromatin Potential Identified by Shared Single-Cell Profiling of RNA and Chromatin. Cell. 2020 Nov 12;183(4):1103-1116.e20. doi: 10.1016/j.cell.2020.09.056. Epub 2020 Oct 23. PubMed PMID: 33098772; PubMed Central PMCID: PMC7669735.

LaFave LM, Kartha VK, Ma S, Meli K, Del Priore I, Lareau C, Naranjo S, Westcott PMK, Duarte FM, Sankar V, Chiang Z, Brack A, Law T, Hauck H, Okimoto A, Regev A, Buenrostro JD^, Jacks T^. Epigenomic State Transitions Characterize Tumor Progression in Mouse Lung Adenocarcinoma. Cancer Cell. 2020 Aug 10;38(2):212-228.e13. doi: 10.1016/j.ccell.2020.06.006. Epub 2020 Jul 23. PubMed PMID: 32707078; PubMed Central PMCID: PMC7641015.

^Co-corresponding authors

LaFave LM, Béguelin W, Koche R, Teater M, Spitzer B, Chramiec A, Papalexi E, Keller MD, Hricik T, Konstantinoff K, Micol JB, Durham B, Knutson SK, Campbell JE, Blum G, Shi X, Doud EH, Krivtsov AV, Chung YR, Khodos I, de Stanchina E, Ouerfelli O, Adusumilli PS, Thomas PM, Kelleher NL, Luo M, Keilhack H, Abdel-Wahab O, Melnick A, Armstrong SA, Levine RL. Reply to "Uveal melanoma cells are resistant to EZH2 inhibition regardless of BAP1 status". Nat Med. 2016 Jun 7;22(6):578-9. doi: 10.1038/nm.4094. PubMed PMID: 27270773.

LaFave LM, Levine RL. Targeting a regulator of protein homeostasis in myeloproliferative neoplasms. Nat Med. 2016 Jan;22(1):20-1. doi: 10.1038/nm.4028. PubMed PMID: 26735404.

LaFave LM, Béguelin W, Koche R, Teater M, Spitzer B, Chramiec A, Papalexi E, Keller MD, Hricik T, Konstantinoff K, Micol JB, Durham B, Knutson SK, Campbell JE, Blum G, Shi X, Doud EH, Krivtsov AV, Chung YR, Khodos I, de Stanchina E, Ouerfelli O, Adusumilli PS, Thomas PM, Kelleher NL, Luo M, Keilhack H, Abdel-Wahab O, Melnick A, Armstrong SA, Levine RL. Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med. 2015 Nov;21(11):1344-9. doi: 10.1038/nm.3947. Epub 2015 Oct 5. PubMed PMID: 26437366; PubMed Central PMCID: PMC4636469.

Meyer SC, Keller MD, Woods BA, LaFave LM, Bastian L, Kleppe M, Bhagwat N, Marubayashi S, Levine RL. Genetic studies reveal an unexpected negative regulatory role for Jak2 in thrombopoiesis. Blood. 2014 Oct 2;124(14):2280-4. doi: 10.1182/blood-2014-03-560441. Epub 2014 Aug 12. PubMed PMID: 25115888; PubMed Central PMCID: PMC4183987.

Abdel-Wahab O, Gao J, Adli M, Dey A, Trimarchi T, Chung YR, Kuscu C, Hricik T, Ndiaye-Lobry D, LaFave LM, Koche R, Shih AH, Guryanova OA, Kim E, Li S, Pandey S, Shin JY, Telis L, Liu J, Bhatt PK, Monette S, Zhao X, Mason CE, Park CY, Bernstein BE, Aifantis I, Levine RL. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med. 2013 Nov 18;210(12):2641-59. doi: 10.1084/jem.20131141. Epub 2013 Nov 11. PubMed PMID: 24218140; PubMed Central PMCID: PMC3832937.

LaFave LM, Levine RL. Mining the epigenetic landscape in ALL. Nat Genet. 2013 Nov;45(11):1269-70. doi: 10.1038/ng.2808. PubMed PMID: 24165727.

LaFave LM, Levine RL. JAK2 the future: therapeutic strategies for JAK-dependent malignancies. Trends Pharmacol Sci. 2012 Nov;33(11):574-82. doi: 10.1016/ Epub 2012 Sep 17. Review. PubMed PMID: 22995223.

Dey A, Seshasayee D, Noubade R, French DM, Liu J, Chaurushiya MS, Kirkpatrick DS, Pham VC, Lill JR, Bakalarski CE, Wu J, Phu L, Katavolos P, LaFave LM, Abdel-Wahab O, Modrusan Z, Seshagiri S, Dong K, Lin Z, Balazs M, Suriben R, Newton K, Hymowitz S, Garcia-Manero G, Martin F, Levine RL, Dixit VM. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science. 2012 Sep 21;337(6101):1541-6. doi: 10.1126/science.1221711. Epub 2012 Aug 9. PubMed PMID: 22878500; PubMed Central PMCID: PMC5201002.

Koppikar P, Bhagwat N, Kilpivaara O, Manshouri T, Adli M, Hricik T, Liu F, Saunders LM, Mullally A, Abdel-Wahab O, Leung L, Weinstein A, Marubayashi S, Goel A, Gönen M, Estrov Z, Ebert BL, Chiosis G, Nimer SD, Bernstein BE, Verstovsek S, Levine RL. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012 Sep 6;489(7414):155-9. doi: 10.1038/nature11303. PubMed PMID: 22820254; PubMed Central PMCID: PMC3991463.

Abdel-Wahab O*, Adli M*, LaFave LM*, Gao J, Hricik T, Shih AH, Pandey S, Patel JP, Chung YR, Koche R, Perna F, Zhao X, Taylor JE, Park CY, Carroll M, Melnick A, Nimer SD, Jaffe JD, Aifantis I, Bernstein BE, Levine RL. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012 Aug 14;22(2):180-93. doi: 10.1016/j.ccr.2012.06.032. PubMed PMID: 22897849; PubMed Central PMCID: PMC3422511.

*Co-first authors

Dawson MA, Bannister AJ, Saunders L, Wahab OA, Liu F, Nimer SD, Levine RL, Göttgens B, Kouzarides T, Green AR. Nuclear JAK2. Blood. 2011 Dec 22;118(26):6987-8. doi: 10.1182/blood-2011-10-385278. PubMed PMID: 22194397; PubMed Central PMCID: PMC4729533.

Abuzeid WM, Davis S, Tang AL, Saunders L, Brenner JC, Lin J, Fuchs JR, Light E, Bradford CR, Prince ME, Carey TE. Sensitization of head and neck cancer to cisplatin through the use of a novel curcumin analog. Arch Otolaryngol Head Neck Surg. 2011 May;137(5):499-507. doi: 10.1001/archoto.2011.63. PubMed PMID: 21576562; PubMed Central PMCID: PMC3298372.

Brenner JC, Graham MP, Kumar B, Saunders LM, Kupfer R, Lyons RH, Bradford CR, Carey TE. Genotyping of 73 UM-SCC head and neck squamous cell carcinoma cell lines. Head Neck. 2010 Apr;32(4):417-26. doi: 10.1002/hed.21198. PubMed PMID: 19760794; PubMed Central PMCID: PMC3292176.

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