Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity

Peter van Galen; Volker Hovestadt; Marc H Wadsworth Ii; Travis K Hughes; Gabriel K Griffin; Sofia Battaglia; Julia A Verga; Jason Stephansky; Timothy J Pastika; Jennifer Lombardi Story; Geraldine S Pinkus; Olga Pozdnyakova; Ilene Galinsky; Richard M Stone; Timothy A Graubert; Alex K Shalek; Jon C Aster; Andrew A Lane; Bradley E Bernstein

doi:10.1016/j.cell.2019.01.031

Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity

Cell. 2019 Mar 7;176(6):1265-1281.e24. doi: 10.1016/j.cell.2019.01.031. Epub 2019 Feb 28.

Authors

Peter van Galen¹, Volker Hovestadt¹, Marc H Wadsworth Ii², Travis K Hughes², Gabriel K Griffin³, Sofia Battaglia¹, Julia A Verga¹, Jason Stephansky⁴, Timothy J Pastika⁴, Jennifer Lombardi Story⁵, Geraldine S Pinkus⁶, Olga Pozdnyakova⁶, Ilene Galinsky⁷, Richard M Stone⁷, Timothy A Graubert⁵, Alex K Shalek², Jon C Aster⁸, Andrew A Lane⁹, Bradley E Bernstein¹⁰

Affiliations

¹ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Ludwig Center at Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
³ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Ludwig Center at Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁴ Ludwig Center at Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁶ Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁷ Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁸ Ludwig Center at Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁹ Ludwig Center at Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁰ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Ludwig Center at Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: bernstein.bradley@mgh.harvard.edu.

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease that resides within a complex microenvironment, complicating efforts to understand how different cell types contribute to disease progression. We combined single-cell RNA sequencing and genotyping to profile 38,410 cells from 40 bone marrow aspirates, including 16 AML patients and five healthy donors. We then applied a machine learning classifier to distinguish a spectrum of malignant cell types whose abundances varied between patients and between subclones in the same tumor. Cell type compositions correlated with prototypic genetic lesions, including an association of FLT3-ITD with abundant progenitor-like cells. Primitive AML cells exhibited dysregulated transcriptional programs with co-expression of stemness and myeloid priming genes and had prognostic significance. Differentiated monocyte-like AML cells expressed diverse immunomodulatory genes and suppressed T cell activity in vitro. In conclusion, we provide single-cell technologies and an atlas of AML cell states, regulators, and markers with implications for precision medicine and immune therapies. VIDEO ABSTRACT.

Keywords: acute myeloid leukemia; cancer genetics; genotyping; immunity; leukemia stem cells; single-cell RNA-sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Base Sequence / genetics
Bone Marrow
Bone Marrow Cells / cytology
Cell Line, Tumor
Disease Progression
Exome Sequencing / methods
Female
Genotype
Humans
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / immunology
Leukemia, Myeloid, Acute / physiopathology
Machine Learning
Male
Middle Aged
Mutation
Prognosis
RNA
Signal Transduction
Single-Cell Analysis / methods
Transcriptome / genetics*
Tumor Microenvironment

Substances

RNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding