The efficiency of murine MLL-ENL–driven leukemia initiation changes with age and peaks during neonatal development

Abstract

MLL rearrangements are translocation mutations that cause both acute lymphoblastic leukemia and acute myeloid leukemia (AML). These translocations can occur as sole clonal driver mutations in infant leukemias, suggesting that fetal or neonatal hematopoietic progenitors may be exquisitely sensitive to transformation by MLL fusion proteins. To test this possibility, we used transgenic mice to induce one translocation product, MLL-ENL, during fetal, neonatal, juvenile and adult stages of life. When MLL-ENL was induced in fetal or neonatal mice, almost all died of AML. In contrast, when MLL-ENL was induced in adult mice, most survived for >1 year despite sustained transgene expression. AML initiation was most efficient when MLL-ENL was induced in neonates, and even transient suppression of MLL-ENL in neonates could prevent AML in most mice. MLL-ENL target genes were induced more efficiently in neonatal progenitors than in adult progenitors, consistent with the distinct AML initiation efficiencies. Interestingly, transplantation stress mitigated the developmental barrier to leukemogenesis. Since fetal/neonatal progenitors were highly competent to initiate MLL-ENL–driven AML, we tested whether Lin28b, a fetal master regulator, could accelerate leukemogenesis. Surprisingly, Lin28b suppressed AML initiation rather than accelerating it. This may explain why MLL rearrangements often occur before birth in human infant leukemia patients, but transformation usually does not occur until after birth, when Lin28b levels decline. Our findings show that the efficiency of MLL-ENL–driven AML initiation changes through the course of pre- and postnatal development, and developmental programs can be manipulated to impede transformation.

Infant Acute Myeloid Leukemia: A Unique Clinical and Biological Entity

“…To understand the mechanistic role of these different molecular lesions, mouse models have been developed using gene editing to create transgenic mice. In parallel, patients derived samples have been used to generate xenotransplants in immunocompromised mice (PDX) [ 5 , 6 , 7 ]. These transgenic mice have helped understanding the role of the different fusions in leukemic transformation.…”

“…During fetal life hematopoiesis, the fetal liver supports self-renewal and differentiation of hematopoietic stem cells and multipotent progenitors (HSC/MPPs). Oncogenic events, mainly fusions, occurring in these fetal liver progenitors impact leukemia phenotype [ 5 , 7 ]. How these fusions impact transcription, disrupt transcription factor balance and promote leukemogenesis may reveal opportunities for treatment.…”

“…How these fusions impact transcription, disrupt transcription factor balance and promote leukemogenesis may reveal opportunities for treatment. Thus, targeted approaches could interfere with oncogenic determinants to improve treatment efficiency of infant leukemia often characterized by very poor outcome [ 5 , 7 ].…”

The MLL/SET family and haematopoiesis

“…For example, the neonatal microenvironment can potentiate AMLs generated by retroviral transduction of murine HSPC with MLL-AF9 or MLL-ENL for mixed-lineage leukaemia output [ 131 ]. Furthermore, a MLL-ENL knock-in model showed that leukaemia initiates more efficiently from foetal and neonatal cells as compared to their adult counterparts, owing to younger HSPCs being more competent at activating the required oncogenic programme [ 160 ].…”

Only Hematopoietic Stem and Progenitor Cells from Cord Blood Are Susceptible to Malignant Transformation by MLL-AF4 Translocations

“…In humanized mouse models, Horton et al could show that human cord blood (huCB) cells were more susceptible for a retroviral MLL-AF9 immortalization, whereas retrovirally transduced huBM cells failed to immortalize in vitro and did not develop leukemia in vivo [ 9 ]. Similarly, by using mouse cells and an MLL-ENL fusion transcript Okeyo-Owuor et al could demonstrate that the efficiency of MLL-ENL -driven AML changes with age with a peak shortly after birth [ 10 ]. In addition, the respective fusion partner has potential influence on leukemia development, as we and others could demonstrate its important role on the resultant phenotype: ENL exclusively led to ALL, whereas AF9 presented as AML, ALL or mixed phenotype in mouse xenograft models [ 11 , 12 ].…”