Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

Alejandra Sanjuan-Pla, Clara Bueno, Cristina Prieto, Pamela Acha, Ronald W. Stam, Rolf Marschalek, Pablo Menéndez

Onderzoeksoutput: Bijdrage aan tijdschriftArtikel recenserenpeer review

93 Citaten (Scopus)

Samenvatting

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 clinicalmanagement and survival (∼85-90%) of childhood B-ALL, the outcome of infants withMLL-rearranged (MLL-r) B-ALL remains dismal, with overall survival <35%. Among MLL-r infantB-ALL, t(4;11)1 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-sequentialhit" model, t(4;11) alone might be sufficient to spawn leukemia. The stable genome of these patients suggests that, in infant developmental cancer, one "bighit" 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)1 infant B-ALL with an emphasis on its origin, genetics, and disease models.

Originele taal-2Engels
Pagina's (van-tot)2676-2685
Aantal pagina's10
TijdschriftBlood
Volume126
Nummer van het tijdschrift25
DOI's
StatusGepubliceerd - 17 dec. 2015
Extern gepubliceerdJa

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