Exploring the paradox of MLL-driven leukemias in infants versus children and adults
Acute lymphoblastic leukemia (ALL) now boasts 90% cure rates in children—except for infants under one year. Their survival plummets below 50%, primarily due to leukemias driven by MLL (KMT2A) gene rearrangements like MLL-AF4 1 8 . This paradox—identical mutations causing vastly different outcomes based on age—has puzzled researchers for decades. Groundbreaking studies now reveal that the developmental origin of blood stem cells—fetal liver, cord blood, or adult bone marrow—holds the key. These microenvironments create permissive or resistant settings for MLL-driven transformation, rewriting our understanding of leukemia initiation.
Infant ALL survival rates are less than 50%, compared to 90% in older children, primarily due to MLL rearrangements.
MLL (Mixed Lineage Leukemia) gene rearrangements account for 70-80% of infant ALL cases, compared to only 5-10% in older children and adults.
The MLL gene regulates blood development by activating critical genes like HOX clusters through histone H3K4 methylation 7 . When chromosomal translocations fuse MLL to partners like AF4 or AF9, the resulting fusion proteins hijack this machinery:
The fusion protein recruits DOT1L, an enzyme adding aberrant H3K79 methylation, activating oncogenes.
The fusion protein blocks differentiation, locking cells in a primitive, proliferative state.
The same fusion behaves differently in fetal versus adult cells.
Key Insight: Infant MLL leukemias require fewer mutations than adult leukemias because fetal hematopoietic cells are intrinsically primed for transformation 1 .
A pivotal 2021 Nature Communications study recreated infant MLL-AF4 leukemia using human fetal liver cells 1 8 :
| Cell Source | Translocation Efficiency | Cell Expansion | Latency to Transformation |
|---|---|---|---|
| Fetal Liver | >80% | 900-fold ↑ | 3 weeks |
| Cord Blood | 70-75% | 500-fold ↑ | 4-5 weeks |
| Adult Bone Marrow | <20% | Minimal growth | No transformation 2 |
Umbilical cord blood—rich in fetal-like stem cells—shows intermediate susceptibility:
MLL-AF4 transforms cord blood HSCs but fails in adult bone marrow HSCs 2
FFAR2 tumor suppressor is epigenetically silenced in cord blood but active in adult cells, blocking immortalization
Cord blood transplants cure leukemias but carry a rare risk of donor cell leukemia (0.1% incidence) 9
| Feature | Fetal Liver | Cord Blood | Adult Bone Marrow |
|---|---|---|---|
| HOX gene expression | High (fetal programs) | Moderate | Low |
| Dependency on LIN28B | Critical 1 | Partial | Minimal |
| Self-renewal capacity | Infinite | Prolonged | Limited |
| Therapeutic resistance | Extreme | Moderate | Lower |
While adult HSCs resist MLL-AF4 transformation, they depend on MLL for homeostasis:
Inducible Mll knockout causes fatal bone marrow failure in 3 weeks 7
MLL maintains HSC quiescence but promotes progenitor proliferation
Committed lymphoid/myeloid cells survive MLL loss, but multipotent progenitors die
Mouse Model Insight: MLL-AF9 transforms both fetal liver and adult bone marrow cells but produces distinct diseases—mixed-lineage leukemia from fetal cells versus myeloid leukemia from adult cells 5 .
Understanding cell-of-origin differences is driving new strategies:
Disrupt MLL fusion complexes
Target fetal-specific pathways in infants
Reinforce adult cell resistance
Delete susceptibility factors pre-transplant
Cord blood transplants save lives in diverse populations—41% of MSKCC's recipients are non-European 6 . Balancing their curative potential against rare donor-derived leukemia requires deeper knowledge of origin biology.
MLL leukemias exemplify how developmental context overrides genetic determinism. The same mutation acts as a "time bomb" in fetal liver, a "slow fuse" in cord blood, and a "dud" in adult bone marrow. As researcher Dr. Teresa Marafioti noted: "Infant MLL-AF4 isn't just leukemia with a fusion; it's a fetal disease that coopts developmental programs for malignancy." Unraveling these programs offers hope for infants—and lessons for cancer biology far beyond leukemia.
For further reading, see Nature Communications 12:6905 (2021) and Cancers 12:1487 (2020).