REAGENT or RESOURCE	SOURCE	IDENTIFIER
Antibodies
Lineage Cell Detection Mixture-Biotin, mouse	Miltenyi Biotech	Cat#130-092-613
Streptavidin APC/Cy7	Southern Biotech	Cat#7100-19S
cKit-APC	eBioscience	Cat#17-1171-83
Sca1-PerCp-Cy5.5	Biolegend	Cat#108124
CD48-PE-Dazzle 594	Biolegend	Cat#103438
CD135-PE	Biolegend	Cat#135305
CD150-PE-Cy7	Biolegend	Cat#115913
CD16/32-PE-Cy7	eBioscience	Cat#25-0161
CD34-FITC	eBioscience	Cat#11-0341
CD45.1(Ly5.1)-EF450	eBioscience	Cat#48-0453
CD45.2(Ly5.2)-PE	Biolegend	Cat#12-0454-82
CD45.1(Ly5.1)-PE	BD Biosciences	Cat#553776
CD45.2(Ly5.2)-PE-Cy7	Biolegend	Cat#109829
CD3-FITC	Biolegend	Cat# 100203
CD19-APC	BD Biosciences	Cat#550993
Gr1-APC-Cy7	Biolegend	Cat#108423
CD11b-PerCp-Cy5.5	BD Biosciences	Cat#561114
CD4-APC	Biolegend	Cat#100516
CD8a-PerCp-C5.5	BD Biosciences	Cat#551162
CD19-APC-H7	BD Biosciences	Cat#560143
CD43 (Ly-48) MicroBeads, mouse	Miltenyi Biotech	Cat#130-049-801
CD43-biotin (clone S7, RUO)	BD Biosciences	Cat#553269
B220-Pacific Blue	BD Biosciences	Cat#558108
CD45.2-FITC	Biolegend	Cat#11-0454-82
Anti-phospho-Histone H2A.X (Ser139) Antibody, clone JBW301	Millipore	Cat#05-636-I; RRID:AB_2755003
Rabbit Polyclonal anti-53BP1 antibody	Novus Biologicals	Cat#NB100-304; RRID:AB_1659862
Mouse Monoclonal Anti-USP15 antibody	Abcam	Cat#ab56900
Rabbit Polyclonal Anti-USP15 antibody	Abcam	Cat#ab71713
Rabbit Polyclonal Anti-FUS antibody	Novus Biologicals	Cat# NB100-565
Alpha-Tubulin Mouse monoclonal antibody	Sigma- Aldrich	Cat#T90026
Goat anti-mouse HRP	Life technologies	Cat# 626520
Normal Rabbit IgG 2729S	Cell Signaling Technology	Cat#2729S
Alexa Fluor 568 goat anti–mouse	Life Technologies	Cat#A-11004
Alexa Fluor 488 goat anti–rabbit	Life Technologies	Cat#A-11008
Chemicals, Peptides, and Recombinant Proteins
Mitomycin C	Santa Cruz Biotechnology, Inc.	Cat# sc-3514
Topotecan	Santa Cruz Biotechnology, Inc.	Cat# sc-204919A
Resazurin Sodium Salt	Sigma	Cat# R7017
Bortezomid	Biomol	Cat#Cay10008822
Cisplatin solution	Accord-Healthcare	https://www.accord-healthcare.com/
Recombinant murine SCF	PrepoTech	Cat# 250-03
Recombinant murine TPO	PrepoTech	Cat# 315-14
Recombinant murine Flt3 ligand	PrepoTech	Cat#250-31L
Critical Commercial Assays
4D-Nucleofector® Kit	Lonza	Cat# V4XP-3032
USP15 Gene Knockout Kit V2 (MV4-11 cells genome editing, Figures 7H and 7I).	Synthego	N/A
DNeasy Blood & Tissue Kit	QIAGEN	Cat# 69504
FuGENE® HD Transfection Reagent	Promega	Cat# E2311
AlamarBlueTM Cell Viability reagent	Thermo Fisher Scientific	Cat#DAL1100
Streptavidin MicroBeads	Miltenyi Bio- tec	Cat#130-074-101
LS MACS® Columns for magnetic cell isolation	Miltenyi Bio- tec	Cat# 130-042-401
AMPure XP solid-phase reversible immobilization kit (SPRI)	Beckman Coulter	Cat# A63881
Deposited Data
RNA sequencing data from K562 and KBM7 cells upon USP15 knockdown by siRNAs	This paper	GEO: GSE160524
RNA sequencing data from LSK cells from Usp15+/+ and Usp15−/− mice	This paper	GEO: GSE160525
RNA sequencing data from LSK cells and B cells from Wild Type mice	Lancini et al., 2016	GEO: GSE58495
Mass spectrometry data, USP15 interactome	This paper	ProteomeXchange: PXD020612
CCLE DeMap v19q1	Broad Institute	https://depmap.org/portal/download/
cBioPortal	Cerami et al., 2012	https://www.cbioportal.org/
Cancer Cell Line Encyclopedia (CCLE)	Broad Institute	https://portals.broadinstitute.org/ccle
Database of hematopoietic cells in health and disease	Hemaexplorer	http://servers.binf.ku.dk/bloodspot/
Single Cell Expression Atlas	Papatheodorou et al., 2020	https://www.ebi.ac.uk/gxa/sc/home
Experimental Models: Cell Lines
KBM7 chronic myelogenous leukemia (CML) cells	Dr. Thijn R. Brummelkamp lab (NKI, Amsterdam)	Blomen et al., 2015
K562 chronic myelogenous leukemia (CML) cells	Dr. Thijn R. Brummelkamp lab (NKI, Amsterdam)	Blomen et al., 2015
MV4-11 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
Kasumi 1 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
MONO-MAC 6 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
GDM-1 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
HL-60 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
GF-D8 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
THP-1 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
KG-1 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
KG-1A Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
ML-2 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
MONO-MAC-1 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
OCI-AML2 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
OCI-AML5 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
M-07e Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
EOL-1 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
PLB-985 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
SKNO-1 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
MOLM-13 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
PL-21 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
MOLM-14 Acute myeloid leukemia (AML) cells	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
NB4	Dr. Saverio Minucci lab (IEO, Milan)	Ravasio et al., 2020
Primary mouse Non-small Cell Lung Cancer (NSCLC) KPE cells KrasG12D/+;Trp53−/−;EED−/− genetic background	Dr. Michela Serresi, Dr. Gaetano Gargiulo (MDC, Berlin)	Serresi et al., 2016
U2OS osteosarcoma cells	Dr. Maarten van Lohuizen lab (NKI, Amsterdam)	N/A
Experimental Models: Organisms/Strains
Mouse: Usp15 knockout	This paper	MGI: Usp15 < em1Nki >; MGI:5810631; B6J-Usp15 < em1Nki >
Mouse: C57BL/6J-Ly5.2 (C57BL/6J) Wild Type	The Jackson Laboratory	Stock No: 000664
Mouse: C57BL/6-Ly5.1 Wild Type	The Jackson Laboratory	Stock No: 002014
Oligonucleotides
Primer sequences for Illumina sequencing multiplexing strategy: see Table S4	This paper	N/A
Mouse Usp15 knockout: 5′ CRISPR-guide (gRNA): TCTTCTTCCACTAGCCGTAGCGG	This paper	N/A
Mouse Usp15 knockout 3′: CRISPR-guide (gRNA): GTCACTTGATACGATAGCGCCGG	This paper	N/A
Mouse Usp15: Forward: 5′-TCCAGTAGGAGTGAACCCGC-3′	This paper	N/A
Mouse Usp15: Reverse knockout allele: 5′-AGGTGGCTGAGAGTGAGAGCAGG-3′	This paper	N/A
Mouse Usp15, Reverse Wild type allele: 5′-GCCTTCCGCCATCTTCTTCCAC-3′	This paper	N/A
Human USP15 siRNAs: siGENOME Human USP15 (9958) siRNA-SMART pool	Dharmacon	M-006066-01
siGENOME Non-Targeting siRNA Control Pool#2	Dharmacon	D-001206-14-05
Human USP15 shRNA#1: TAAACCAGCATCCTGAATGG	This paper	N/A
Human USP15 shRNA#2: TTTCATGAACTCAGCTATTC	This paper	N/A
Human sgRNA (sg01) targeting sequence: USP15ex3, 5′-AAGGTGTTCCTTAAGTGACT-3′ (U2OS cells genome editing; Figure S7).	Human Brunello CRISPR knockout pooled library; CRISPR Design; CRISPRscan	Addgene #73178; http://crispr.mit.edu/http://www.crisprscan.org
Human USP15, Pair of complementary DNA oligos: USP15 Forward 5′-caccgAAGGTGTTCCTTAAGTGACT-3′ (U2OS cells genome editing; Figure S7).	This paper	N/A
Human USP15, Pair of complementary DNA oligos: USP15 Reverse 5′-aaacAGTCACTTAAGGAACACCTTc-3′ (U2OS cells genome editing; Figure S7).	This paper	N/A
ASK-FN2 5′-CGGCCTTTTTACGGTTCCTG-3′ (U2OS cells genome editing; Figure S7).	Addgene	https://www.addgene.org/53062/sequences/
TIDE analysis: Human genomic region surrounding USP15 gRNA-targeted region: Forward 5′- GTTAGTGTTACAATTCTTCCAATACGG-3′	This paper	N/A
TIDE analysis: Human genomic region surrounding USP15 gRNA-targeted region: Reverse, 5′GTTTTATCAAAAACAGTGCAGCACAG-3′	This paper	N/A
TIDE analysis: Sanger sequencing Primer 5′-TTACAATTCTTCCAATACGGCCCAG-3′	This paper	N/A
qRT-PCR – mouse HPRT Forward: 5′-CTGGTGAAAGGACCTCTCG-3′	This paper	N/A
qRT-PCR - mouse HPRT Reverse: 5′-TGAAGTACTCATTATAGTCAAGGGCA-3′	This paper	N/A
qRT-PCR mouse Usp15 A Forward: 5′- TGTGGCTTAAGTAACTTGGGAAA-3′	This paper	N/A
qRT-PCR mouse Usp15 A Reverse: 5′-AAGTGGAGGTGTGTTGCTCA-3′	This paper	N/A
qRT-PCR mouse Usp15 B Forward: 5′-TCAGCTGGTACACACTGATGG-3′	This paper	N/A
qRT-PCR mouse Usp15 B Reverse: 5′-TGCTTTACAAACATACCCTGTTCT-3′	This paper	N/A
Primers used in Figures S6G and S6H for validation of RNA-seq results are available upon request.	This paper	N/A
Recombinant DNA
RNAi Consortium library (TRC Mm1.0)	Sigma-Aldrich, MO	MISSION® TRC Mm1.0)
pLKO.1-puro	Sigma-Aldrich, MO	SHC001
pLKO.1-puro USP15sh15	Sigma-Aldrich, MO	TRCN0000033215
pLKO.1-puro USP15sh16	Sigma-Aldrich, MO	TRCN0000033216
pLKO.1-puro USP15sh17	Sigma-Aldrich, MO	TRCN0000033217
pSpCas9(BB)-2A-GFP (PX458) plasmid	Addgene	Cat#48138
Plasmid: pLV[Exp]-Puro-H1/TO > hUSP15shRNA#1-UBC > TetR(ns):T2A:EGFP	This paper	N/A
Plasmid: pLV[Exp]-Puro-H1/TO > hUSP15shRNA#2-UBC > TetR(ns):T2A:EGFP	This paper	N/A
Software and Algorithms
TIDE software	Dr. Bas van Steensel lab (NKI, Amsterdam)	https://tide.nki.nl/
MaxQuant software package version 1.6.3.4	Max Planck Institute of Biochemistry (Cox and Mann, 2008)	https://www.maxquant.org
Reactome pathway analysis tool v3.7, database release 73	Fabregat et al., 2017	https://reactome.org/
R v3.5	https://cran.r-project.org/	https://cran.r-project.org/
Progeny v1.6	Schubert et al., 2018	https://bioconductor.org/packages/release/bioc/html/progeny.html
Limma v3.36	Ritchie et al., 2015	https://bioconductor.org/packages/release/bioc/html/limma.html
ImageJ software (version:2.0)	NIH; Dr. Bram van den Broek (NKI, Amsterdam)	https://imagej.nih.gov/ij/
FACS data analysis	FlowJo	https://www.flowjo.com/ FlowJo Software version 10.0.8r1. (Tree Star)
RNA-seq mapping pipeline	TopHat2.1, Genome build 38 Ensembl gtf version 77	https://ccb.jhu.edu/software/tophat/index.shtml
RNA-seq differential expression analysis	R package	R; DEGseq 10.18129/B9.bioc.DEGseq
RNA-seq genecounts	Itreecount	https://github.com/NKI-GCF/itreecount
Prism 7.0	GraphPad	https://www.graphpad.com/scientific-software/prism/
CRISPR/Cas9 design tools	CRISPR Design; CRISPRscan	http://crispr.mit.edu/http://www.crisprscan.org
Other
X-ray irradiation	Faxitron	MultiRad 225 X-ray irradiation system
Time-lapse imaging and proliferation assays	Essen BioScience	IncuCyte FRL