Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1-po
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RESEARCH
Open Access
Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1positive pediatric leukemia identifies drugtargetable transcription factor activities Juha Mehtonen1†, Susanna Teppo2†, Mari Lahnalampi1, Aleksi Kokko1, Riina Kaukonen3, Laura Oksa2, Maria Bouvy-Liivrand1, Alena Malyukova4, Artturi Mäkinen2, Saara Laukkanen2, Petri I. Mäkinen5, Samuli Rounioja6, Pekka Ruusuvuori2, Olle Sangfelt4, Riikka Lund3, Tapio Lönnberg3, Olli Lohi2,7 and Merja Heinäniemi1*
Abstract Background: Tight regulatory loops orchestrate commitment to B cell fate within bone marrow. Genetic lesions in this gene regulatory network underlie the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). The initial genetic hits, including the common translocation that fuses ETV6 and RUNX1 genes, lead to arrested cell differentiation. Here, we aimed to characterize transcription factor activities along the B-lineage differentiation trajectory as a reference to characterize the aberrant cell states present in leukemic bone marrow, and to identify those transcription factors that maintain cancer-specific cell states for more precise therapeutic intervention. Methods: We compared normal B-lineage differentiation and in vivo leukemic cell states using single cell RNAsequencing (scRNA-seq) and several complementary genomics profiles. Based on statistical tools for scRNA-seq, we benchmarked a workflow to resolve transcription factor activities and gene expression distribution changes in healthy bone marrow lymphoid cell states. We compared these to ALL bone marrow at diagnosis and in vivo during chemotherapy, focusing on leukemias carrying the ETV6-RUNX1 fusion. (Continued on next page)
* Correspondence: [email protected] † Juha Mehtonen and Susanna Teppo contributed equally to this work. 1 Institute of Biomedicine, School of Medicine, University of Eastern Finland, Yliopistonranta 1, FI-70211 Kuopio, Finland Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) appli
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