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

Okeyo-Owuor, Theresa; Li, Yanan; Patel, Riddhi M.; Yang, Wei; Casey, Emily B.; Cluster, Andrew S.; Porter, Shaina N.; Bryder, David LU and Magee, Jeffrey A. (2019) In Blood Advances 3(15). p.2388-2399
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... (More)

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 MLLENL- 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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organization
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Contribution to journal
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published
subject
in
Blood Advances
volume
3
issue
15
pages
12 pages
publisher
American Society of Hematology
external identifiers
  • scopus:85070765932
ISSN
2473-9529
DOI
10.1182/bloodadvances.2019000554
language
English
LU publication?
yes
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77e4441a-1430-4ce5-908f-001e551264ac
date added to LUP
2019-09-09 10:11:37
date last changed
2019-09-17 05:00:53
@article{77e4441a-1430-4ce5-908f-001e551264ac,
  abstract     = {<p>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 &gt;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 MLLENL- driven AML initiation changes through the course of pre- and postnatal development, and developmental programs can be manipulated to impede transformation.</p>},
  author       = {Okeyo-Owuor, Theresa and Li, Yanan and Patel, Riddhi M. and Yang, Wei and Casey, Emily B. and Cluster, Andrew S. and Porter, Shaina N. and Bryder, David and Magee, Jeffrey A.},
  issn         = {2473-9529},
  language     = {eng},
  number       = {15},
  pages        = {2388--2399},
  publisher    = {American Society of Hematology},
  series       = {Blood Advances},
  title        = {The efficiency of murine MLL-ENL-driven leukemia initiation changes with age and peaks during neonatal development},
  url          = {http://dx.doi.org/10.1182/bloodadvances.2019000554},
  volume       = {3},
  year         = {2019},
}