Hematopoietic Stem Cells Are Intrinsically Protected against MLL-ENL-Mediated Transformation.
(2014) In Cell Reports 9(4). p.1246-1255- Abstract
- Studies of developmental pathways of hematopoietic stem cells (HSCs) have defined lineage relationships throughout the blood system. This is relevant to acute myeloid leukemia (AML), where aggressiveness and therapeutic responsiveness can be influenced by the initial stage of transformation. To address this, we generated a mouse model in which the mixed-lineage leukemia/eleven-nineteen-leukemia (MLL-ENL) transcription factor can be conditionally activated in any cell type. We show that AML can originate from multiple hematopoietic progenitor subsets with granulocytic and monocytic potential, and that the normal developmental position of leukemia-initiating cells influences leukemic development. However, disease failed to arise from HSCs.... (More)
- Studies of developmental pathways of hematopoietic stem cells (HSCs) have defined lineage relationships throughout the blood system. This is relevant to acute myeloid leukemia (AML), where aggressiveness and therapeutic responsiveness can be influenced by the initial stage of transformation. To address this, we generated a mouse model in which the mixed-lineage leukemia/eleven-nineteen-leukemia (MLL-ENL) transcription factor can be conditionally activated in any cell type. We show that AML can originate from multiple hematopoietic progenitor subsets with granulocytic and monocytic potential, and that the normal developmental position of leukemia-initiating cells influences leukemic development. However, disease failed to arise from HSCs. Although it maintained or upregulated the expression of target genes associated with leukemic development, MLL-ENL dysregulated the proliferative and repopulating capacity of HSCs. Therefore, the permissiveness for development of AML may be associated with a narrower window of differentiation than was previously appreciated, and hijacking the self-renewal capacity of HSCs by a potent oncogene is insufficient for leukemic development. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4913111
- author
- Ugale, Amol LU ; Norddahl, Gudmundur LU ; Wahlestedt, Martin LU ; Säwén, Petter LU ; Jaako, Pekka LU ; Pronk, Kees-Jan LU ; Soneji, Shamit LU ; Cammenga, Jörg LU and Bryder, David LU
- organization
-
- Hematopoietic and immunologic developement (research group)
- Department of Experimental Medical Science
- Division of Molecular Medicine and Gene Therapy
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- publishing date
- 2014
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cell Reports
- volume
- 9
- issue
- 4
- pages
- 1246 - 1255
- publisher
- Cell Press
- external identifiers
-
- pmid:25456127
- wos:000345529600009
- scopus:84912066449
- pmid:25456127
- ISSN
- 2211-1247
- DOI
- 10.1016/j.celrep.2014.10.036
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Division of Molecular Medicine and Gene Therapy (013022010), Stem Cell Aging (013212073)
- id
- 5e61697d-38b5-442f-a21f-a4537e787eb9 (old id 4913111)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/25456127?dopt=Abstract
- date added to LUP
- 2016-04-01 15:00:18
- date last changed
- 2022-04-22 06:15:03
@article{5e61697d-38b5-442f-a21f-a4537e787eb9, abstract = {{Studies of developmental pathways of hematopoietic stem cells (HSCs) have defined lineage relationships throughout the blood system. This is relevant to acute myeloid leukemia (AML), where aggressiveness and therapeutic responsiveness can be influenced by the initial stage of transformation. To address this, we generated a mouse model in which the mixed-lineage leukemia/eleven-nineteen-leukemia (MLL-ENL) transcription factor can be conditionally activated in any cell type. We show that AML can originate from multiple hematopoietic progenitor subsets with granulocytic and monocytic potential, and that the normal developmental position of leukemia-initiating cells influences leukemic development. However, disease failed to arise from HSCs. Although it maintained or upregulated the expression of target genes associated with leukemic development, MLL-ENL dysregulated the proliferative and repopulating capacity of HSCs. Therefore, the permissiveness for development of AML may be associated with a narrower window of differentiation than was previously appreciated, and hijacking the self-renewal capacity of HSCs by a potent oncogene is insufficient for leukemic development.}}, author = {{Ugale, Amol and Norddahl, Gudmundur and Wahlestedt, Martin and Säwén, Petter and Jaako, Pekka and Pronk, Kees-Jan and Soneji, Shamit and Cammenga, Jörg and Bryder, David}}, issn = {{2211-1247}}, language = {{eng}}, number = {{4}}, pages = {{1246--1255}}, publisher = {{Cell Press}}, series = {{Cell Reports}}, title = {{Hematopoietic Stem Cells Are Intrinsically Protected against MLL-ENL-Mediated Transformation.}}, url = {{https://lup.lub.lu.se/search/files/4294863/7697124.pdf}}, doi = {{10.1016/j.celrep.2014.10.036}}, volume = {{9}}, year = {{2014}}, }