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

Journal article
Authors T. Okeyo-Owuor
Y. N. Li
R. M. Patel
W. Yang
E. B. Casey
A. S. Cluster
S. N. Porter
David Bryder
J. A. Magee
Published in Blood Advances
Volume 3
Issue 15
Pages 2388-2399
ISSN 2473-9529
Publication year 2019
Published at Sahlgrenska Cancer Center
Pages 2388-2399
Language en
Links dx.doi.org/10.1182/bloodadvances.20...
Keywords hematopoietic stem-cells, acute myeloid-leukemia, gene-expression, profile, self-renewal, h3k79 methylation, lin28b, progenitor, rearrangements, maintenance, mutations, Hematology
Subject categories Hematology

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.

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