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.

Detailed Characterization of Mesenchymal Stem/Stromal Cells from a Large Cohort of AML Patients Demonstrates a Definitive Link to Treatment Outcomes

“…These data confirm that BM-MSCs are not tumor related and that the cell of origin for AML may be an early hematopoietic stem cell or a more committed myeloid progenitor. Three out of the 46 AMLs were pediatric cases, yet still their BM-MSCs were devoid of tumor-specific cytogenetic/molecular alterations, further emphasizing that even in those pediatric cases in which genetic drivers may have a prenatal origin during in utero hematopoietic development, the target cell for transformation seems to be an ontogenically early HSPC (Greaves and Wiemels, 2003, Menendez et al., 2009, Sanjuan-Pla et al., 2015). …”

Relatively favorable prognosis for MLL‐rearranged childhood acute leukemia with reciprocal translocations

“…However, AF4‐MLL transcripts are found in 50–80% of MLL ‐r patients . Whether AF4‐MLL fusion alone functions as MLL‐AF4 as an oncogenic initiating event remains a controversial question . To date, the relationship between patient‐specific multiple MLL rearrangements and clinical prognosis has not yet been elucidated.…”

“…as an oncogenic initiating event remains a controversial question. 20 To date, the relationship between patient-specific multiple MLL rearrangements and clinical prognosis has not yet been elucidated.…”

Concise Reviews: Cancer Stem Cell Targeted Therapies: Toward Clinical Success

“…During oncogenic transformation, alterations in DNA methylation and chromatin can be modulated by both intrinsic and extrinsic cues, and such modifications have been shown as drivers of CSC formation. For instance in mixed lineage leukemia (MLL)‐associated leukemia, chromosomal rearrangements in the histone methyltransferase KMT2A/MLL have been implicated in the formation of LSCs . The DNA methyltransferase family of DNMT1, DNMT3A, and DNMT3B, which are responsible for methylating CpG dinucleotides, are mutated in ~25% of AML patients and lead to the expansion of leukemic stem cells, as does loss of function of the TET proteins which antagonize the DNMT family, suggesting that any disruption of steady state methylation patterns can affect CSC formation.…”