This work was supported by a Quest for Cure grant to L.I.S., J.C.Y.W. and M.D.M. from the Leukemia and Lymphoma Society, and the following grants to L.I.S from: ERC Horizon 2020 MAMLE, Abisch-Frenkel foundation and an American Society of Hematology Scholar Award. Further funding to J.E.D. was provided by the Canada Research Chair Program, Ontario Institute for Cancer Research, the province of Ontario, Canadian Cancer Society, the Canadian Institutes for Health Research and the Ontario Ministry of Health and Long Term Care to UHN, whose views are not expressed here. Work conducted at the Sanger Institute was supported by the Wellcome Trust and UK Medical Research Council. S.A. was personally funded by the Benjamin Pearl fellowship from the McEwen Centre for Regenerative Medicine, G.C. by a Wellcome Trust Clinical PhD Fellowship (WT098051); G.S.V. by a Wellcome Trust Senior Fellowship in Clinical Science (WT095663MA) and a Cancer Research UK Senior Cancer Research Fellowship (C22324/A23015). G.S.V.'s laboratory is also funded by the Kay Kendall Leukaemia Fund and Bloodwise. We thank A. Mitchell and all members of the Dick and Shlush laboratories for comments and T. Hudson for early study planning; G. Barabash for organising the Clalit dataset collaboration. The EPIC study centres were supported by the Hellenic Health Foundation, Regional Government of Asturias, the Regional Government of Murcia (no. 6236), the Spanish Ministry of Health network RTICCC (ISCIII RD12/0036/0018), FEDER funds/European Regional Development Fund (ERDF), “a way to build Europe”, Generalitat de Catalunya, AGAUR 2014SGR726; EPIC Ragusa in Italy-Aire-Onlus Ragusa; Epic Italy-Associazione Italiana per la Ricerca sul Cancro (AIRC) Milan, Italy. S.V.B. and T.J.P. are supported by the Gattuso-Slaight Personalized Cancer Medicine Fund at the Princess Margaret Cancer Centre.

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Nature thanks R. Levine, P. Van Loo and the other anonymous reviewer(s) for their contribution to the peer review of this work.