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ACKNOWLEDGMENTS

We thank D. Curovic, R. Kelly, J. Law, and M. Niit at the Research

Centre for Women's and Infants’Health Biobank (Mount Sinai

Hospital) for sample coordination; B. Chow at the Pathology and

Laboratory Medicine (Mount Sinai Hospital) for assistance with

pathology; M. DSouza and R. Lopez at the Animal Resources

Centre (UHN) for support with mouse work; M. Bergeret, S. Boddeda,

S. Ng, A. Srinath, O. Subedar, A. AuYeung, and S. Zhao at the

SickKids-UHN Flow and Mass Cytometry Facility for assistance with

flow cytometry; B. Apresto at The Centre for Applied Genomics

(SickKids) for sanger sequencing; K. Ho at the Centre for Applied

Genomics (SickKids) for next-generation sequencing; A. Smith

at the Cancer Cytogenetics Laboratory (UHN) for karyotyping;

K. Asoyan, C. Cimafranca, J. Mouatt, M. Peralta, and Y. Yang at the

Pathology Research Program (UHN) and N. Law at the Sttarr

Innovation Centre (UHN) for assistance with histology; M. Bartolini

at the Advanced Optical Microscopy Facility (UHN) for slide

scanning; J. Moffat, K. Brown, and C. Ross at the Donnelly Centre for

supplying the gRNA sequences for the in vivo screen; S. Henikoff at

the Fred Hutchinson Cancer Research Center for supplying the

Protein A-Micrococcal nuclease fusion protein for the Cut&Run

assay; L. Shultz at the Jackson Laboratory for providing NSGW41

mice; the laboratories of S. Chan and F. Notta for sharing equipment;

N. Mbong and A. Mitchell for technical assistance; and H. Hasle

for sharing unpublished work. We thank C. Jones, A. Tikhonova, and

members of the Dick laboratory for comments on the manuscript.

Funding:This work was supported by funds from Human Frontier

Science Program (LT-000601); Alex’s Lemonade Stand Foundation

(19-16679); The Leukemia & Lymphoma Society and The

Leukemia & Lymphoma Society of Canada (3404-21); Portuguese

Foundation for Science and Technology (SFRH/BD/136200/2018);

Princess Margaret Cancer Centre Foundation; Ontario Institute

for Cancer Research through funding provided by the Government

of Ontario; Canadian Institutes for Health Research (Foundation:

154293, Operating Grant 130412, Operating Grant 89932, and

Canada-Japan CEEHRC Teams in Epigenetics of Stem Cells 127882);

International Development Research Centre, Canadian Cancer

Society (703212); Terry Fox Research Institute Program Project

Grant; University of Toronto’s Medicine by Design initiative, which

receives funding from the Canada First Research Excellence Fund;

and a Canada Research Chair.Author contributions:E.W.,

J.E.D., and E.R.L. conceived the project, supervised research, and

wrote the paper. J.A., O.I.G., G.K., and J.C.Y.W. edited the paper.

E.W., J.A., O.I.G., and E.R.L. analyzed experiments. E.W., J.A., S.K.C.,

M.A., S.A.S., and B.A.G. performed in vitro and in vivo experiments.

O.I.G and E.R.L. assisted with mouse work. J.A. performed

morphological analysis. O.I.G. assisted with single-cell assays.

A.M. analyzed ATAC-seq and RNA-seq data. G.K. performed Western

blot assays and Cut&Run assays and prepared miRNA libraries.

J.L.M. assisted with intrafemoral injections. S.A.M. and D.D.D.C.

performed Cut&Run analysis. M.G. and L.S. analyzed miRNA

sequencing data. J.J.F.M. generated smMIP libraries. S.M., J.C.,

and J.K.H. supplied primary TAM samples. M.C.-S.-Y. performed

CRISPR/Cas9 off-target analysis. L.G.-P. assisted with ATAC-seq

library preparations. S.A. performed smMIP analysis. M.A.

performed histopathological analysis. K.C., M.R., P.S., and D.C.

coordinated patient consent and sample collection. J.C.Y.W.

and J.K.H. provided study consultation. J.E.D. secured funding

for this study.Competing interests:D.D.D.C.: Pfizer and Nektar

Therapeutics, research funding; DNAMx, cofounder and shareholder.

J.E.D.: Celgene, research funding; Trillium Therapeutics, advisory

board. All other authors declare no competing interests.Data

and materials availability:Raw sequence data are available at

European Genome-phenome Archive (EGAS00001004780)

and processed data are available at Gene Expression Omnibus

(GSE160096). All other data are available in the manuscript or the

supplementary materials.

SUPPLEMENTARY MATERIALS

science.sciencemag.org/content/373/6551/eabf6202/suppl/DC1

Materials and Methods

Figs. S1 to S15

Tables S1 to S9

References ( 69 – 87 )

MDAR Reproducibility Checklist

7 November 2020; resubmitted 9 March 2021

Accepted 21 May 2021

10.1126/science.abf6202

Wagenblastet al.,Science 373 , eabf6202 (2021) 9 July 2021 13 of 13

RESEARCH | RESEARCH ARTICLE