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Cellular origin and clinical prognostic markers of infant MLLr B-ALL
this mutationally silent iBCP-ALL. This study has clinical implications in the diagnostic risk-stratification of t(4;11)+ iBCP-ALL.
Acknowledgments
We would like to thank the Santander Supercomputing Service for IT support. The human fetal material was provided by the Joint MRC/Wellcome Trust (grant# MR/R006237/1) Human Developmental Biology Resource (http://hdbr.org). This work was supported by the European Research Council (CoG-2014- 646903 to PM; and StG-2014-637904 to IV), the Spanish Ministry of Economy and Competitiveness (SAF-SAF2013- 43065 to PM and SAF2016-76758-R to IV), the Asociación
Española Contra el Cáncer (AECC-CI-2015), FERO Foundation, and the ISCIII (PI14-01191) to CB. PM/IV also acknowledge financial support from The Obra Social La Caixa- Fundaciò Josep Carreras, The Inocente Inocente Foundation, Fundación Ramón Areces and The Generalitat de Catalunya (SGR330). IR was supported by a Programme Grant from Bloodwise (LLR 13001) and by the Oxford NIHR Biomedical Centre based at Oxford University Hospitals NHS Trust and University of Oxford. PM is an investigator of the Spanish Cell Therapy cooperative network (TERCEL). AR was supported by a Clinician Scientist Fellowship from Bloodwise (14041). This work was motivated by our patients and it honors the vital exam- ple given to us by the family of AMC.
References
1. Pui C-H, Evans WE. A 50-year journey to cure childhood acute lymphoblastic leukemia. Semin Hematol. 2013;50(3):185– 196.
2. Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012;120(6):1165–1174.
3. Meyer C, Burmeister T, Gröger D, et al. The MLL recombinome of acute leukemias in 2017. Leukemia. 2018;32(2):273–284.
4. Sanjuan-Pla A, Bueno C, Prieto C, et al. Revisiting the biology of infant t(4;11)/MLL- AF4+ B-cell acute lymphoblastic leukemia. Blood. 2015;126(25):2676–2685.
5. Marschalek R. Mechanisms of leukemogen- esis by MLL fusion proteins. Br J Haematol. 2011;152(2):141–154.
6. Ribeiro RC, Pui CH. Prognostic factors in childhood acute lymphoblastic leukemia. Hematol Pathol. 1993;7(3):121–142.
7. Pieters R, Schrappe M, De Lorenzo P, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 2007;370(9583):240–250.
8. Biondi A, Cimino G, Pieters R, Pui C-H. Biological and therapeutic aspects of infant leukemia. Blood. 2000;96(1):24–33.
9. Milne TA. Mouse models of MLL leukemia: recapitulating the human disease. Blood. 2017;129(16):2217–2223.
10. Nakamura T, Mori T, Tada S, et al. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in tran- scriptional regulation. Mol Cell. 2002;10(5): 1119–1128.
11. Chen CW, Armstrong SA. Targeting DOT1L and HOX gene expression in MLL- rearranged leukemia and beyond. Exp Hematol. 2015;43(8):673–684.
12. McLean CM, Karemaker ID, van Leeuwen F. The emerging roles of DOT1L in leukemia and normal development. Leukemia. 2014;28(11):2131–2138.
13. Krivtsov AV, Feng Z, Lemieux ME, et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer. 2009;14(5):355–368.
14. Greaves MF, Maia AT, Wiemels JL, Ford AM. Leukemia in twins: lessons in natural histo- ry. Blood. 2003;102(7):2321–2333.
15. Ford AM, Ridge SA, Cabrera ME, et al. In utero rearrangements in the trithorax-related
oncogene in infant leukaemias. Nature.
1993;363(6427):358–360.
16. Gale KB, Ford AM, Repp R, et al.
Backtracking leukemia to birth: identifica- tion of clonotypic gene fusion sequences in neonatal blood spots. Proc Natl Acad Sci U S A. 1997;94(25):13950–13954.
17. Bueno C, Montes R, Catalina P, Rodríguez R, Menendez P. Insights into the cellular ori- gin and etiology of the infant pro-B acute lymphoblastic leukemia with MLL-AF4 rearrangement. Leukemia. 2011;25(3):400– 410.
18. Bardini M, Galbiati M, Lettieri A, et al. Implementation of array based whole- genome high-resolution technologies con- firms the absence of secondary copy-number alterations in MLL-AF4-positive infant ALL patients. Leukemia. 2011;25(1):175–178.
19. Dobbins SE, Sherborne AL, Ma YP, et al. The silent mutational landscape of infant MLL- AF4 pro-B acute lymphoblastic leukemia. Genes Chromosom Cancer. 2013;52(10): 954–960.
20. Andersson AK, Ma J, Wang J, et al. The land- scape of somatic mutations in infant MLL- rearranged acute lymphoblastic leukemias. Nat Genet. 2015;47(4):330–337.
21. Lin S, Luo RT, Ptasinska A, et al. Instructive role of MLL-fusion proteins revealed by a model of t(4;11) pro-B acute lymphoblastic leukemia. Cancer Cell. 2016;30(5):737–749.
22. Lin S, Luo RT, Shrestha M, Thirman MJ, Mulloy JC. The full transforming capacity of MLL-Af4 is interlinked with lymphoid line- age commitment. Blood. 2017;130(7):903– 907.
al. Activated KRAS cooperates with MLL- AF4 to promote extramedullary engraftment and migration of cord blood CD34+ HSPC but is insufficient to initiate leukemia. Cancer Res. 2016;76(8):2478–2489.
28. Krivtsov A V., Armstrong SA. MLL translo- cations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007;7(11):823–833.
29. Varela I, Menendez P, Sanjuan-Pla A. Intratumoral heterogeneity and clonal evolu- tion in blood malignancies and solid tumors. Oncotarget. 2017;8(39):66742–66746.
30. Driessen E, Lorenzo P, M C, et al. Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol. Blood. 2009;114(18):3764–3768.
31. Menendez P, Catalina P, Rodríguez R, et al. Bone marrow mesenchymal stem cells from infants with MLL-AF4+ acute leukemia har- bor and express the MLL-AF4 fusion gene. J Exp Med. 2009;206(13):3131–3141.
32. Muñoz-López A, Romero-Moya D, Prieto C, et al. Development refractoriness of MLL- rearranged human B cell acute leukemias to reprogramming into pluripotency. Stem Cell Reports. 2016;7 (4):602–618.
33. Roy A, Cowan G, Mead AJ, et al. Perturbation of fetal liver hematopoietic stem and progenitor cell development by tri- somy 21. Proc Natl Acad Sci U S A. 2012;109(43):17579–17584.
34. Gröbner SN, Worst BC, Weischenfeldt J, et al. The landscape of genomic alterations across childhood cancers. Nature. 2018;555 (7696):321-327.
35. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–
23. Yamamoto H. Successful sustained engraft-
ment after reduced-intensity umbilical cord
blood transplantation for adult patients with 421.
severe aplastic anemia. Blood. 2011;116(26):
6123–6132.
24. Montes R, Ayllón V, Prieto C, et al. Ligand-
independent FLT3 activation does not coop- erate with MLL-AF4 to immortalize/trans- form cord blood CD34+ cells. Leukemia. 2014;28(3):666–674.
25. Bueno C, Montes R, Melen GJ, et al. A human ESC model for MLL-AF4 leukemic fusion gene reveals an impaired early hematopoietic-endothelial specification. Cell Res. 2012;22(6):986–1002.
26. Bueno C, Ayllón V, Montes R, et al. FLT3 activation cooperates with MLL-AF4 fusion protein to abrogate the hematopoietic spec- ification of human ESCs. Blood. 2013;121(19):3867–3878.
27. Prieto C, Stam RWRW, Agraz-Doblas A, et
36. Trentin L, Bresolin S, Giarin E, et al. Deciphering KRAS and NRAS mutated clone dynamics in MLL-AF4 paediatric leukaemia by ultra deep sequencing analy- sis. Sci Rep. 2016;6:34449.
37. Bashford-Rogers RJM, Nicolaou KA, Bartram J, et al. Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia sub- clones from diagnosis to relapse. Leukemia. 2016;30(12):2312–2321.
38. Prelle C, Bursen A, Dingermann T, Marschalek R. Secondary mutations in t(4;11) leukemia patients. Leukemia. 2013;27(6):1425–1427.
39. Stam RW, Schneider P, Hagelstein JAP, et al. Gene expression profiling-based dissection of MLL translocated and MLL germline
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