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Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia
Alejandra Sanjuan-Pla1, Clara Bueno1, Cristina Prieto1
1Josep Carreras Leukemia Research Institute and School of Medicine, University of Barcelona, Barcelona, Spain;
Insights
Infant B-cell acute lymphoblastic leukemia (B-ALL) with the MLL-AF4 fusion is a distinct developmental disease originating prenatally. This aggressive leukemia may arise from a single genetic event, highlighting the role of epigenetics and early developmental vulnerabilities.
Area of Science:
- Pediatric Oncology
- Developmental Biology
- Cancer Genetics
Background:
- Infant B-cell acute lymphoblastic leukemia (B-ALL) accounts for 10% of childhood ALL.
- Mixed-lineage leukemia (MLL) gene rearrangements are common in infant B-ALL.
- Patients with MLL-rearranged (MLL-r) B-ALL, particularly t(4;11)+ harboring MLL-AF4 (MA4), have a dismal prognosis (<35% survival).
Purpose of the Study:
- To review the biology of t(4;11)+ infant B-ALL, focusing on its unique origin, genetics, and disease models.
- To emphasize infant cancers as developmental diseases distinct from adult cancers.
- To explore the potential for a single genetic event and epigenetic contributions in the pathogenesis.
Main Methods:
- Review of existing literature on infant B-ALL, MLL rearrangements, and t(4;11) fusion.
- Analysis of findings from twin studies and blood spot research regarding prenatal origin.
- Examination of whole-genome sequencing data and proposed "big-hit" models.
Main Results:
- Evidence suggests a single prenatal cell of origin for MA4 fusion, explaining short leukemia latency.
- The stable genome in these patients supports a "big-hit" model where t(4;11) alone may initiate leukemia.
- Lack of adequate disease models hinders progress in understanding etiology and pathogenesis.
Conclusions:
- Infant MLL-r B-ALL, especially t(4;11)+, is a distinct developmental malignancy.
- Epigenetics and prenatal origin during critical developmental windows are key factors.
- Further research and improved disease models are crucial for advancing treatment strategies.
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.
