MLL-rearranged infant leukaemia: A ‘thorn in the side’ of a remarkable success story

Siobhan Rice1, Anindita Roy
1Medical Research Council (MRC) Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

Tài liệu tham khảo

Vora, 2013, Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial, Lancet Oncol, 14, 199, 10.1016/S1470-2045(12)70600-9 Burnett, 2013, Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial, J. Clin. Oncol., 31, 3360, 10.1200/JCO.2012.47.4874 Gamis, 2014, Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children's Oncology Group trial AAML0531, J. Clin. Oncol., 32, 3021, 10.1200/JCO.2014.55.3628 Meyer, 2018, The MLL recombinome of acute leukemias in 2017, Leukemia, 32, 273, 10.1038/leu.2017.213 Pieters, 2019, Outcome of infants younger than 1 year with acute lymphoblastic leukemia treated with the Interfant-06 protocol: results from an international phase III randomized study, J. Clin. Oncol., 37, 10.1200/JCO.19.00261 Pieters, 2007, A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial, Lancet, 370, 240, 10.1016/S0140-6736(07)61126-X Dreyer, 2015, Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3), Pediatr. Blood Cancer, 62, 419, 10.1002/pbc.25322 Bueno, 2011, Insights into the cellular origin and etiology of the infant pro-B acute lymphoblastic leukemia with MLL-AF4 rearrangement, Leukemia, 25, 400, 10.1038/leu.2010.284 Sanjuan-Pla, 2015, Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia, Blood, 126, 2676, 10.1182/blood-2015-09-667378 Daser, 2004, Extending the repertoire of the mixed-lineage leukemia gene MLL in leukemogenesis, Genes Dev., 18, 965, 10.1101/gad.1195504 Marschalek, 2011, Mechanisms of leukemogenesis by MLL fusion proteins, Br. J. Haematol., 152, 141, 10.1111/j.1365-2141.2010.08459.x Milne, 2017, Mouse models of MLL leukemia: recapitulating the human disease, Blood, 129, 2217, 10.1182/blood-2016-10-691428 Brown, 2019, How I treat infant leukemia, Blood, 133, 205, 10.1182/blood-2018-04-785980 Forgione, 2020, KMT2A rearranged acute lymphoblastic leukaemia: unravelling the genomic complexity and heterogeneity of this high-risk disease, Cancer Lett., 469, 410, 10.1016/j.canlet.2019.11.005 Winters, 2017, MLL-rearranged leukemias-an update on science and clinical approaches, Front. Pediatr., 5, 4, 10.3389/fped.2017.00004 Creutzig, 2012, Favorable outcome in infants with AML after intensive first- and second-line treatment: an AML-BFM study group report, Leukemia, 26, 654, 10.1038/leu.2011.267 Kawasaki, 2001, Superior outcome of infant acute myeloid leukemia with intensive chemotherapy: results of the Japan Infant Leukemia Study Group, Blood, 98, 3589, 10.1182/blood.V98.13.3589 Bader, 1979, US cancer incidence and mortality in the first year of life, Am J Dis Child, 133, 157 Brown, 2013, Treatment of infant leukemias: challenge and promise, Hematology Am Soc Hematol Educ Program, 2013, 596, 10.1182/asheducation-2013.1.596 Roberts, 2018, Neonatal leukaemia, Br. J. Haematol., 182, 170, 10.1111/bjh.15246 Silverman, 2007, Acute lymphoblastic leukemia in infancy, Pediatr. Blood Cancer, 49, 1070, 10.1002/pbc.21352 Hilden, 2006, Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group, Blood, 108, 441, 10.1182/blood-2005-07-3011 Harrison, 2010, Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council treatment trials AML 10 and 12, J. Clin. Oncol., 28, 2674, 10.1200/JCO.2009.24.8997 Moorman, 2010, Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial, Lancet Oncol, 11, 429, 10.1016/S1470-2045(10)70066-8 Iacobucci, 2017, Genetic basis of acute lymphoblastic leukemia, J. Clin. Oncol., 35, 975, 10.1200/JCO.2016.70.7836 Jansen, 2007, Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement, Leukemia, 21, 633, 10.1038/sj.leu.2404578 Behm, 1996, Human homologue of the rat chondroitin sulfate proteoglycan, NG2, detected by monoclonal antibody 7.1, identifies childhood acute lymphoblastic leukemias with t(4;11)(q21;q23) or t(11;19)(q23;p13) and MLL gene rearrangements, Blood, 87, 1134, 10.1182/blood.V87.3.1134.bloodjournal8731134 Menendez, 2011, Expression of NG2 antigen in MLL-rearranged acute leukemias: how complex does it get?, Leuk. Res., 35, 989, 10.1016/j.leukres.2011.03.015 Wuchter, 2001, Impact of CD133 (AC133) and CD90 expression analysis for acute leukemia immunophenotyping, Haematologica, 86, 154 Prieto, 2018, NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL, Leukemia, 32, 633, 10.1038/leu.2017.294 Ramakers-van Woerden, 2004, In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype, Leukemia, 18, 521, 10.1038/sj.leu.2403253 Mann, 2010, Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study, Blood, 116, 2644, 10.1182/blood-2010-03-273532 Gardner, 2016, Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy, Blood, 127, 2406, 10.1182/blood-2015-08-665547 Jacoby, 2016, CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity, Nat. Commun., 7, 10.1038/ncomms12320 Rayes, 2016, Lineage switch in MLL-rearranged infant Leukemia following CD19-directed therapy, Pediatr. Blood Cancer, 63, 1113, 10.1002/pbc.25953 Rossi, 2012, Lineage switch in childhood acute leukemia: an unusual event with poor outcome, Am. J. Hematol., 87, 890, 10.1002/ajh.23266 Borkhardt, 2002, Infant acute lymphoblastic leukemia - combined cytogenetic, immunophenotypical and molecular analysis of 77 cases, Leukemia, 16, 1685, 10.1038/sj.leu.2402595 Van der Velden, 2009, Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol, Leukemia, 23, 1073, 10.1038/leu.2009.17 Armstrong, 2002, MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia, Nat. Genet., 30, 41, 10.1038/ng765 Armstrong, 2004, FLT3 mutations in childhood acute lymphoblastic leukemia, Blood, 103, 3544, 10.1182/blood-2003-07-2441 Chillon, 2012, Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia, Leukemia, 26, 2360, 10.1038/leu.2012.161 Stam, 2005, Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia, Blood, 106, 2484, 10.1182/blood-2004-09-3667 Brown, 2005, FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression, Blood, 105, 812, 10.1182/blood-2004-06-2498 2016, Addition of FLT3 inhibitor lestaurtinib to post-induction chemotherapy does not improve outcomes in MLL-rearranged infant acute lymphoblastic leukemia (ALL): AALL0631, a Children's Oncology Group study Yokoyama, 2005, The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis, Cell, 123, 207, 10.1016/j.cell.2005.09.025 Krivtsov, 2019, A menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia, Cancer Cell, 36, 660, 10.1016/j.ccell.2019.11.001 Milne, 2005, Leukemogenic MLL fusion proteins bind across a broad region of the Hox a9 locus, promoting transcription and multiple histone modifications, Cancer Res., 65, 11367, 10.1158/0008-5472.CAN-05-1041 Bitoun, 2007, The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling, Hum. Mol. Genet., 16, 92, 10.1093/hmg/ddl444 Krivtsov, 2008, H3K79 methylation profiles define murine and human MLL-AF4 leukemias, Cancer Cell, 14, 355, 10.1016/j.ccr.2008.10.001 Stein, 2015, Mixed lineage rearranged leukaemia: pathogenesis and targeting DOT1L, Curr. Opin. Hematol., 22, 92, 10.1097/MOH.0000000000000123 Shukla, 2016, Final report of phase 1 study of the DOT1L inhibitor, pinometostat (EPZ-5676), in children with relapsed or refractory MLL-r acute Leukemia, Blood, 128, 2780, 10.1182/blood.V128.22.2780.2780 Stein, 2014, The DOT1L inhibitor EPZ-5676: safety and activity in relapsed/refractory patients with MLL-rearranged Leukemia, Blood, 124, 387, 10.1182/blood.V124.21.387.387 Stein, 2018, The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia, Blood, 131, 2661, 10.1182/blood-2017-12-818948 Stumpel, 2009, Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options, Blood, 114, 5490, 10.1182/blood-2009-06-227660 Schafer, 2010, Promoter hypermethylation in MLL-r infant acute lymphoblastic leukemia: biology and therapeutic targeting, Blood, 115, 4798, 10.1182/blood-2009-09-243634 Dawson, 2011, Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia, Nature, 478, 529, 10.1038/nature10509 Picaud, 2015, Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy, Cancer Res., 75, 5106, 10.1158/0008-5472.CAN-15-0236 Zuber, 2011, RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia, Nature, 478, 524, 10.1038/nature10334 Cruickshank, 2017, Systematic chemical and molecular profiling of MLL-rearranged infant acute lymphoblastic leukemia reveals efficacy of romidepsin, Leukemia, 31, 40, 10.1038/leu.2016.165 Berthon, 2016, Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study, Lancet Haematol, 3, e186, 10.1016/S2352-3026(15)00247-1 Burke, 2014, Invasive Candida infections in pediatric patients treated on the pilot study of decitabine and vorinostat with chemotherapy for relapsed ALL: a report from the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Consortium, Blood, 124, 3650, 10.1182/blood.V124.21.3650.3650 Liu, 2014, Proteasome inhibitors evoke latent tumor suppression programs in pro-B MLL leukemias through MLL-AF4, Cancer Cell, 25, 530, 10.1016/j.ccr.2014.03.008 Koss, 2014, Targeted inhibition of the MLL transcriptional complex by proteosome inhibitors elicits a high response rate in relapsed/refractory MLL rearranged leukemia, Blood, 124, 972, 10.1182/blood.V124.21.972.972 Gore, 2018, Survival after blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia, Blood Cancer J, 8, 80, 10.1038/s41408-018-0117-0 Topp, 2011, Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival, J. Clin. Oncol., 29, 2493, 10.1200/JCO.2010.32.7270 Kantarjian, 2017, Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia, N. Engl. J. Med., 376, 836, 10.1056/NEJMoa1609783 Mejstrikova, 2017, CD19-negative relapse of pediatric B-cell precursor acute lymphoblastic leukemia following blinatumomab treatment, Blood Cancer J, 7, 659, 10.1038/s41408-017-0023-x Wayne, 2017, Phase 1 study of the anti-CD22 immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic leukemia, Blood, 130, 1620, 10.1182/blood-2017-02-749101 Hoelzer, 2012, Anti-CD22 therapy in acute lymphoblastic leukaemia, Lancet Oncol, 13, 329, 10.1016/S1470-2045(12)70010-4 Raetz, 2015, Re-induction chemoimmunotherapy with epratuzumab in relapsed acute lymphoblastic leukemia (ALL): phase II results from Children's Oncology Group (COG) study ADVL04P2, Pediatr. Blood Cancer, 62, 1171, 10.1002/pbc.25454 Shah, 2015, Characterization of CD22 expression in acute lymphoblastic leukemia, Pediatr. Blood Cancer, 62, 964, 10.1002/pbc.25410 Fry, 2018, CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy, Nat. Med., 24, 20, 10.1038/nm.4441 Lee, 2015, T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial, Lancet, 385, 517, 10.1016/S0140-6736(14)61403-3 Gardner, 2017, Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults, Blood, 129, 3322, 10.1182/blood-2017-02-769208 Maude, 2018, Tisagenlecleucel in children and young adults with B-cell lymphoblastic Leukemia, N. Engl. J. Med., 378, 439, 10.1056/NEJMoa1709866 Ghorashian, 2019, Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR, Nat. Med., 25, 1408, 10.1038/s41591-019-0549-5 Qasim, 2017, Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells, Sci. Transl. Med., 9, 10.1126/scitranslmed.aaj2013 Li, 2018, TanCAR T cells targeting CD19 and CD133 efficiently eliminate MLL leukemic cells, Leukemia, 32, 2012, 10.1038/s41375-018-0212-z Godfrey, 2020, H3K79me2/3 controls enhancer-promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells, Leukemia, 10.1038/s41375-020-0808-y Bueno, 2019, CD133-directed CAR T-cells for MLL leukemia: on-target, off-tumor myeloablative toxicity, Leukemia, 33, 2090, 10.1038/s41375-019-0418-8 Wang, 2018, CD133-directed CAR T cells for advanced metastasis malignancies: a phase I trial, Oncoimmunology, 7, 10.1080/2162402X.2018.1440169 Lopez-Millan, 2019, NG2 antigen is a therapeutic target for MLL-rearranged B-cell acute lymphoblastic leukemia, Leukemia, 33, 1557, 10.1038/s41375-018-0353-0 Mann, 2007, Acute lymphoblastic leukemia with t(4;11) in children 1 year and older: the 'big sister' of the infant disease?, Leukemia, 21, 642, 10.1038/sj.leu.2404577 Pui, 2002, Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region, Lancet, 359, 1909, 10.1016/S0140-6736(02)08782-2 Pui, 2014, A revised definition for cure of childhood acute lymphoblastic leukemia, Leukemia, 28, 2336, 10.1038/leu.2014.142 Gale, 1997, Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots, Proc. Natl. Acad. Sci. U. S. A., 94, 13950, 10.1073/pnas.94.25.13950 Mansur, 2015, Distinctive genotypes in infants with T-cell acute lymphoblastic leukaemia, Br. J. Haematol., 171, 574, 10.1111/bjh.13613 Greaves, 2003, Leukemia in twins: lessons in natural history, Blood, 102, 2321, 10.1182/blood-2002-12-3817 Greaves, 2003, Origins of chromosome translocations in childhood leukaemia, Nat. Rev. Cancer, 3, 639, 10.1038/nrc1164 Ford, 1993, In utero rearrangements in the trithorax-related oncogene in infant leukaemias, Nature, 363, 358, 10.1038/363358a0 Greaves, 2005, In utero origins of childhood leukaemia, Early Hum. Dev., 81, 123, 10.1016/j.earlhumdev.2004.10.004 Greaves, 2018, A causal mechanism for childhood acute lymphoblastic leukaemia, Nat. Rev. Cancer, 18, 471, 10.1038/s41568-018-0015-6 Mullighan, 2007, Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia, Nature, 446, 758, 10.1038/nature05690 Wiemels, 1999, Prenatal origin of acute lymphoblastic leukaemia in children, Lancet, 354, 1499, 10.1016/S0140-6736(99)09403-9 Ma, 2013, Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia, Proc. Natl. Acad. Sci. U. S. A., 110, 7429, 10.1073/pnas.1221099110 Andersson, 2015, The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias, Nat. Genet., 47, 330, 10.1038/ng.3230 Agraz-Doblas, 2019, Unravelling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis, Haematologica, 104, 1176, 10.3324/haematol.2018.206375 Dobbins, 2013, The silent mutational landscape of infant MLL-AF4 pro-B acute lymphoblastic leukemia, Genes Chromosomes Cancer, 52, 954, 10.1002/gcc.22090 Lansdorp, 1993, Ontogeny-related changes in proliferative potential of human hematopoietic cells, J. Exp. Med., 178, 787, 10.1084/jem.178.3.787 Muench, 1994, Expression of CD33, CD38, and HLA-DR on CD34+ human fetal liver progenitors with a high proliferative potential, Blood, 83, 3170, 10.1182/blood.V83.11.3170.3170 Harrison, 1997, Relative to adult marrow, fetal liver repopulates nearly five times more effectively long-term than short-term, Exp. Hematol., 25, 293 Nicolini, 1999, Unique differentiation programs of human fetal liver stem cells shown both in vitro and in vivo in NOD/SCID mice, Blood, 94, 2686, 10.1182/blood.V94.8.2686.420k15_2686_2695 Holyoake, 1999, Functional differences between transplantable human hematopoietic stem cells from fetal liver, cord blood, and adult marrow, Exp. Hematol., 27, 1418, 10.1016/S0301-472X(99)00078-8 Beyer, 2017, Comparison of human hematopoietic reconstitution in different strains of immunodeficient mice, Stem Cells Dev., 26, 102, 10.1089/scd.2016.0083 Li, 2015, A developmental switch between fetal and adult B lymphopoiesis, Ann. N. Y. Acad. Sci., 1362, 8, 10.1111/nyas.12769 McWilliams, 2013, The human fetal lymphocyte lineage: identification by CD27 and LIN28B expression in B cell progenitors, J. Leukoc. Biol., 94, 991, 10.1189/jlb.0113048 Yuan, 2012, Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis, Science, 335, 1195, 10.1126/science.1216557 Copley, 2013, The Lin28b-let-7-Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells, Nat. Cell Biol., 15, 916, 10.1038/ncb2783 Viswanathan, 2009, Lin28 promotes transformation and is associated with advanced human malignancies, Nat. Genet., 41, 843, 10.1038/ng.392 Zhou, 2013, LIN28/LIN28B: an emerging oncogenic driver in cancer stem cells, Int. J. Biochem. Cell Biol., 45, 973, 10.1016/j.biocel.2013.02.006 Rossi, 2003, B lymphopoiesis is active throughout human life, but there are developmental age-related changes, Blood, 101, 576, 10.1182/blood-2002-03-0896 O'Byrne, 2019, Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs, Blood, 134, 1059, 10.1182/blood.2019001289 Notta, 2016, Distinct routes of lineage development reshape the human blood hierarchy across ontogeny, Science, 351, aab2116, 10.1126/science.aab2116 2018, HemaSphere, 2, 1, 10.1097/HS9.0000000000000060 Asma, 1984, Development of pre-B and B lymphocytes in the human fetus, Clin. Exp. Immunol., 56, 407 Nunez, 1996, B cells are generated throughout life in humans, J. Immunol., 156, 866, 10.4049/jimmunol.156.2.866 Malouf, 2018, The fetal liver lymphoid-primed multipotent progenitor provides the prerequisites for the initiation of t(4;11) MLL-AF4 infant leukemia, Haematologica, 103, e571, 10.3324/haematol.2018.191718 Bardini, 2015, Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement, Leukemia, 29, 38, 10.1038/leu.2014.154 Castor, 2005, Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia, Nat. Med., 11, 630, 10.1038/nm1253 Hotfilder, 2005, Leukemic stem cells in childhood high-risk ALL/t(9;22) and t(4;11) are present in primitive lymphoid-restricted CD34+CD19- cells, Cancer Res., 65, 1442, 10.1158/0008-5472.CAN-04-1356 le Viseur, 2008, In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties, Cancer Cell, 14, 47, 10.1016/j.ccr.2008.05.015 Menendez, 2009, Bone marrow mesenchymal stem cells from infants with MLL-AF4+ acute leukemia harbor and express the MLL-AF4 fusion gene, J. Exp. Med., 206, 3131, 10.1084/jem.20091050 Bueno, 2019, Enhanced hemato-endothelial specification during human embryonic differentiation through developmental cooperation between AF4-MLL and MLL-AF4 fusions, Haematologica, 104, 1189, 10.3324/haematol.2018.202044 Bueno, 2012, A human ESC model for MLL-AF4 leukemic fusion gene reveals an impaired early hematopoietic-endothelial specification, Cell Res., 22, 986, 10.1038/cr.2012.4 Lin, 2017, The full transforming capacity of MLL-Af4 is interlinked with lymphoid lineage commitment, Blood, 130, 903, 10.1182/blood-2017-04-777185 Alhaj Hussen, 2017, Molecular and functional characterization of lymphoid progenitor subsets reveals a bipartite architecture of human lymphopoiesis, Immunity, 47, 680, 10.1016/j.immuni.2017.09.009 Boiers, 2018, A human IPS model implicates embryonic B-myeloid fate restriction as developmental susceptibility to B acute lymphoblastic leukemia-associated ETV6-RUNX1, Dev. Cell, 44, 362, 10.1016/j.devcel.2017.12.005 Roy, 2012, Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21, Proc. Natl. Acad. Sci. U. S. A., 109, 17579, 10.1073/pnas.1211405109 Sanz, 2003, Human cord blood CD34+Pax-5+ B-cell progenitors: single-cell analyses of their gene expression profiles, Blood, 101, 3424, 10.1182/blood-2002-07-2244 Sanz, 2010, Ordering human CD34+CD10-CD19+ pre/pro-B-cell and CD19- common lymphoid progenitor stages in two pro-B-cell development pathways, Proc. Natl. Acad. Sci. U. S. A., 107, 5925, 10.1073/pnas.0907942107 Wolfl, 2018, Spontaneous reversion of a lineage switch following an initial blinatumomab-induced ALL-to-AML switch in MLL-rearranged infant ALL, Blood Adv, 2, 1382, 10.1182/bloodadvances.2018018093 Montes, 2011, Enforced expression of MLL-AF4 fusion in cord blood CD34+ cells enhances the hematopoietic repopulating cell function and clonogenic potential but is not sufficient to initiate leukemia, Blood, 117, 4746, 10.1182/blood-2010-12-322230 Montes, 2014, Ligand-independent FLT3 activation does not cooperate with MLL-AF4 to immortalize/transform cord blood CD34+ cells, Leukemia, 28, 666, 10.1038/leu.2013.346 Prieto, 2016, 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., 76, 2478, 10.1158/0008-5472.CAN-15-2769 Bueno, 2013, FLT3 activation cooperates with MLL-AF4 fusion protein to abrogate the hematopoietic specification of human ESCs, Blood, 121, 3867, 10.1182/blood-2012-11-470146 Somervaille, 2006, Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia, Cancer Cell, 10, 257, 10.1016/j.ccr.2006.08.020 Krivtsov, 2013, Cell of origin determines clinically relevant subtypes of MLL-rearranged AML, Leukemia, 27, 852, 10.1038/leu.2012.363 Chen, 2011, Modeling human infant MLL leukemia in mice: leukemia from fetal liver differs from that originating in postnatal marrow, Blood, 117, 3474, 10.1182/blood-2010-11-317529 Horton, 2013, MLL-AF9-mediated immortalization of human hematopoietic cells along different lineages changes during ontogeny, Leukemia, 27, 1116, 10.1038/leu.2012.343 Barabe, 2007, Modeling the initiation and progression of human acute leukemia in mice, Science, 316, 600, 10.1126/science.1139851 Hyrenius-Wittsten, 2019, FLT3(N676K) drives acute myeloid leukemia in a xenograft model of KMT2A-MLLT3 leukemogenesis, Leukemia, 33, 2310, 10.1038/s41375-019-0465-1 Lin, 2016, Instructive role of MLL-fusion proteins revealed by a model of t(4;11) pro-B acute lymphoblastic leukemia, Cancer Cell, 30, 737, 10.1016/j.ccell.2016.10.008 Barrett, 2016, Mll-AF4 confers enhanced self-renewal and lymphoid potential during a restricted window in development, Cell Rep., 16, 1039, 10.1016/j.celrep.2016.06.046 Rowe, 2019, The developmental stage of the hematopoietic niche regulates lineage in MLL-rearranged leukemia, J. Exp. Med., 216, 527, 10.1084/jem.20181765