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MLL-ENL-mediated leukemia initiation at the interface of lymphoid commitment

Ugale, A. LU ; Säwén, P. LU ; Dudenhöffer-Pfeifer, M. LU ; Wahlestedt, M. LU ; Norddahl, G. L. LU and Bryder, D. LU (2017) In Oncogene 36. p.3207-3212
Abstract

Translocations involving the mixed lineage leukemia-1 are recurrent events in acute leukemia and associate with lymphoid (ALL), myeloid (AML) or mixed lineage (MLL) subtypes. Despite an association with ALL in humans, murine MLL fusion models are persistently restricted to AML. We here explored this issue using an inducible mixed lineage leukemia-eleven nineteen leukemia (MLL-ENL) mouse model. Although multiple progenitor cell types with myeloid potential are potent AML leukemia-initiating cells, also the earliest lymphoid progenitors were capable of initiating AML. This ability to evoke a latent myeloid potential in the earliest lymphoid progenitors was lost upon further lymphoid commitment. At the same time, more downstream/committed... (More)

Translocations involving the mixed lineage leukemia-1 are recurrent events in acute leukemia and associate with lymphoid (ALL), myeloid (AML) or mixed lineage (MLL) subtypes. Despite an association with ALL in humans, murine MLL fusion models are persistently restricted to AML. We here explored this issue using an inducible mixed lineage leukemia-eleven nineteen leukemia (MLL-ENL) mouse model. Although multiple progenitor cell types with myeloid potential are potent AML leukemia-initiating cells, also the earliest lymphoid progenitors were capable of initiating AML. This ability to evoke a latent myeloid potential in the earliest lymphoid progenitors was lost upon further lymphoid commitment. At the same time, more downstream/committed lymphoid precursors also failed to initiate lymphoid leukemia. Co-expression of MLL-ENL with a constitutively active RAS allele, the most common co-mutation in MLL fusion leukemias, could influence on both disease latency and lineage assignment of developing leukemia in what appears to be a mutation-order-dependent manner. Finally, CEBPB-mediated transdifferentation of committed and otherwise leukemia-incompetent B-cell progenitors imbued these cells with leukemic competence for AML. Therefore, apart from providing detailed insight into the differential responsiveness of candidate target cells to a first-hit MLL fusion event, our data warrants caution to therapeutic approaches based on the concept of transdifferentiation.Oncogene advance online publication, 9 January 2017; doi:10.1038/onc.2016.470.

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publication status
published
subject
in
Oncogene
volume
36
pages
3207 - 3212
publisher
Nature Publishing Group
external identifiers
  • scopus:85008635946
  • wos:000402617900012
ISSN
0950-9232
DOI
10.1038/onc.2016.470
language
English
LU publication?
yes
id
22271803-1b01-401b-9782-e605c91e1dc4
date added to LUP
2017-03-02 10:47:09
date last changed
2018-01-07 11:53:39
@article{22271803-1b01-401b-9782-e605c91e1dc4,
  abstract     = {<p>Translocations involving the mixed lineage leukemia-1 are recurrent events in acute leukemia and associate with lymphoid (ALL), myeloid (AML) or mixed lineage (MLL) subtypes. Despite an association with ALL in humans, murine MLL fusion models are persistently restricted to AML. We here explored this issue using an inducible mixed lineage leukemia-eleven nineteen leukemia (MLL-ENL) mouse model. Although multiple progenitor cell types with myeloid potential are potent AML leukemia-initiating cells, also the earliest lymphoid progenitors were capable of initiating AML. This ability to evoke a latent myeloid potential in the earliest lymphoid progenitors was lost upon further lymphoid commitment. At the same time, more downstream/committed lymphoid precursors also failed to initiate lymphoid leukemia. Co-expression of MLL-ENL with a constitutively active RAS allele, the most common co-mutation in MLL fusion leukemias, could influence on both disease latency and lineage assignment of developing leukemia in what appears to be a mutation-order-dependent manner. Finally, CEBPB-mediated transdifferentation of committed and otherwise leukemia-incompetent B-cell progenitors imbued these cells with leukemic competence for AML. Therefore, apart from providing detailed insight into the differential responsiveness of candidate target cells to a first-hit MLL fusion event, our data warrants caution to therapeutic approaches based on the concept of transdifferentiation.Oncogene advance online publication, 9 January 2017; doi:10.1038/onc.2016.470.</p>},
  author       = {Ugale, A. and Säwén, P. and Dudenhöffer-Pfeifer, M. and Wahlestedt, M. and Norddahl, G. L. and Bryder, D.},
  issn         = {0950-9232},
  language     = {eng},
  month        = {01},
  pages        = {3207--3212},
  publisher    = {Nature Publishing Group},
  series       = {Oncogene},
  title        = {MLL-ENL-mediated leukemia initiation at the interface of lymphoid commitment},
  url          = {http://dx.doi.org/10.1038/onc.2016.470},
  volume       = {36},
  year         = {2017},
}