Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1-positive pediatric leukemia identifies drug-targetable transcription factor activities.

Genome Medicine
J. MehtonenMerja Heinaniemi

Abstract

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. We compared normal B-lineage differentiation and in vivo leukemic cell states using single cell RNA-sequencing (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. We show that lymphoid cell transcription factor activities ...Continue Reading

References

Mar 5, 1998·Nature·V M BraudA J McMichael
Jun 5, 2002·Genome Research·W James KentDavid Haussler
Oct 21, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Menno C van ZelmJacques J M van Dongen
Sep 6, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Marit E HystadErlend B Smeland
Jan 23, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Clare PridansStephen L Nutt
Mar 5, 2008·Cancer Research·Christine WasylykBohdan Wasylyk
Dec 23, 2008·Seminars in Hematology·Guillermo Garcia-ManeroHagop Kantarjian
Feb 20, 2009·The Journal of Biological Chemistry·Katharine H WrightonXin-Hua Feng
Mar 6, 2009·Genome Biology·Ben LangmeadSteven L Salzberg
Mar 17, 2009·The Journal of Clinical Investigation·Anthony M FordMel Greaves
May 4, 2010·Nature Biotechnology·Cory Y McLeanGill Bejerano
Jan 12, 2011·Nature Biotechnology·James T RobinsonJill P Mesirov
May 4, 2012·Leukemia·J J M van DongenUNKNOWN EuroFlow Consortium (EU-FP6, LSHB-CT-2006-018708)
Apr 17, 2013·BMC Bioinformatics·Edward Y ChenAvi Ma'ayan
Jun 25, 2013·Nature Cell Biology·Annamaria BiroccioEric Gilson
Mar 4, 2014·Nature Genetics·Birgit KnoechelBradley E Bernstein
Jan 20, 2015·Nature Genetics·Matthew K IyerArul M Chinnaiyan
May 20, 2015·Nature Immunology·Srividya SwaminathanMarkus Müschen
May 24, 2015·Bioinformatics·Laleh HaghverdiFabian J Theis
Jul 16, 2015·Journal of Biomedical Science·Yen-Chi Liu, Soo-Chen Cheng

❮ Previous
Next ❯

Methods Mentioned

BETA
RNA-seq
flow cytometry
PCR
genotyping
scRNA-seq
FACS
flow
PCA
ChIP-seq
RNA Assay

Key Resources (RRID) Mentioned

AB_27378607
AB_1582279

Software Mentioned

GRO
Genome Browser
UMAP
R
ENCODE
FastX
Velocyto
ComplexHeatmap
mnnpy
Enrichr

Related Concepts

Related Feeds

B cells: Gene Expression

B lymphocytes are white blood cells that play a role in the adaptive immune system by secreting antibodies. Here is the latest research on gene expression in B cells.