TY - JOUR
T1 - Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia
AU - Sanjuan-Pla, Alejandra
AU - Bueno, Clara
AU - Prieto, Cristina
AU - Acha, Pamela
AU - Stam, Ronald W.
AU - Marschalek, Rolf
AU - Menéndez, Pablo
N1 - Publisher Copyright:
© 2015 by The American Society of Hematology.
PY - 2015/12/17
Y1 - 2015/12/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84951278550&partnerID=8YFLogxK
U2 - 10.1182/blood-2015-09-667378
DO - 10.1182/blood-2015-09-667378
M3 - Review article
C2 - 26463423
AN - SCOPUS:84951278550
SN - 0006-4971
VL - 126
SP - 2676
EP - 2685
JO - Blood
JF - Blood
IS - 25
ER -