title: Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia.
abstract: Infant B-cell acute lymphoblastic leukemia (B-ALL) accounts for 10% of childhood ALL. The genetic hallmark of most infant B-ALL is chromosomal rearrangements of the mixed-lineage leukemia (MLL) gene. Despite improvement in the clinical management and survival (∼85-90%) of childhood B-ALL, the outcome of infants with MLL-rearranged (MLL-r) B-ALL remains dismal, with overall survival <35%. Among MLL-r infant B-ALL, t(4;11)+ patients harboring the fusion MLL-AF4 (MA4) display a particularly poor prognosis and a pro-B/mixed phenotype. Studies in monozygotic twins and archived blood spots have provided compelling evidence of a single cell of prenatal origin as the target for MA4 fusion, explaining the brief leukemia latency. Despite its aggressiveness and short latency, current progress on its etiology, pathogenesis, and cellular origin is limited as evidenced by the lack of mouse/human models recapitulating the disease phenotype/latency. We propose this is because infant cancer is from an etiologic and pathogenesis standpoint distinct from adult cancer and should be seen as a developmental disease. This is supported by whole-genome sequencing studies suggesting that opposite to the view of cancer as a "multiple-and-sequential-hit" model, t(4;11) alone might be sufficient to spawn leukemia. The stable genome of these patients suggests that, in infant developmental cancer, one "big-hit" might be sufficient for overt disease and supports a key contribution of epigenetics and a prenatal cell of origin during a critical developmental window of stem cell vulnerability in the leukemia pathogenesis. Here, we revisit the biology of t(4;11)+ infant B-ALL with an emphasis on its origin, genetics, and disease models.
authors.affiliation: Josep Carreras Leukemia Research Institute and School of Medicine, University of Barcelona, Barcelona, Spain;
authors.forename: Alejandra
authors.initials: A
authors.lastname: Sanjuan-Pla
authors.affiliation: Josep Carreras Leukemia Research Institute and School of Medicine, University of Barcelona, Barcelona, Spain;
authors.forename: Clara
authors.initials: C
authors.lastname: Bueno
authors.affiliation: Josep Carreras Leukemia Research Institute and School of Medicine, University of Barcelona, Barcelona, Spain;
authors.forename: Cristina
authors.initials: C
authors.lastname: Prieto
authors.affiliation: Josep Carreras Leukemia Research Institute and School of Medicine, University of Barcelona, Barcelona, Spain;
authors.forename: Pamela
authors.initials: P
authors.lastname: Acha
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands;
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Stam
authors.affiliation: Institute of Pharmaceutical Biology, Goethe-University, Frankfurt/Main, Germany; and.
authors.forename: Rolf
authors.initials: R
authors.lastname: Marschalek
authors.affiliation: Josep Carreras Leukemia Research Institute and School of Medicine, University of Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Menéndez
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D007223:Infant; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D035602:Transcriptional Elongation Factors; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D011495:Histone-Lysine N-Methyltransferase