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Oncogenic fusion proteins expressed in immature hematopoietic cells fail to recapitulate the transcriptional changes observed in human AML.

Rapin N, Porse BT - Oncogenesis (2014)

Bottom Line: Here, we critically assessed the potential of such in vitro models using an integrative bioinformatics approach.Surprisingly, we found that the gene-expression profiles of CD34+ human HSPCs transformed with the potent oncogenic fusion proteins AML-ETO or MLL-AF9, only weakly resembled those derived from primary AML samples.Hence, our work raises concerns as to the relevance of the use of in vitro transduced cells to study the impact of transcriptional deregulation in human AML.

View Article: PubMed Central - PubMed

Affiliation: 1] The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark [2] Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark [3] Department of Biology, Faculty of Natural Sciences, The Bioinformatics Centre, University of Copenhagen, Copenhagen, Denmark [4] Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

ABSTRACT
Reciprocal chromosomal translocations are observed in one-third of acute myeloid leukemia (AML) cases. Targeting and understanding the effects of the resulting aberrant oncogenic fusion proteins may help developing drugs against specific leukemic subtypes, as demonstrated earlier by the use of ATRA in acute promyelocytic leukemia. Hematopoietic stem/progenitor (HSPCs) cells transduced with oncogenic fusion genes are regarded as promising in vitromodels of their corresponding AML subtypes. Here, we critically assessed the potential of such in vitro models using an integrative bioinformatics approach. Surprisingly, we found that the gene-expression profiles of CD34+ human HSPCs transformed with the potent oncogenic fusion proteins AML-ETO or MLL-AF9, only weakly resembled those derived from primary AML samples. Hence, our work raises concerns as to the relevance of the use of in vitro transduced cells to study the impact of transcriptional deregulation in human AML.

No MeSH data available.


Related in: MedlinePlus

Pathway-centric comparison of transcriptional changes in AML blasts and CD34+ cells transduced with the same oncogenes. Median gene-expression fold change of selected MsigDB gene signatures that are significantly (P<1e−5) enriched among genes found to be deregulated in AML blasts samples. Fold change is computed relative to controls for transduced cells, and relative to the closest normal counterpart for AMLs blasts.
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fig2: Pathway-centric comparison of transcriptional changes in AML blasts and CD34+ cells transduced with the same oncogenes. Median gene-expression fold change of selected MsigDB gene signatures that are significantly (P<1e−5) enriched among genes found to be deregulated in AML blasts samples. Fold change is computed relative to controls for transduced cells, and relative to the closest normal counterpart for AMLs blasts.

Mentions: Finally, we took a pathway-centric approach to compare the transcriptional changes in AML blasts with those in transduced CD34+ cells. Specifically, we first identified gene signatures found to be significantly (P<1e−5, hypergeometric test) deregulated in AML blasts versus normal cells.16 We next report their median fold changes, relative to control and nearest normal counterparts, in transduced CD34+ cells and in a subset of AML blast samples, respectively (Figure 2). Strikingly, while gene signatures associated with cell cycle processes are generally downregulated in AML blasts, we note that the transduced CD34+ cells only exhibit a transient downregulation of these pathways. Such behavior could potentially be associated with an adaptation to the culture conditions. Similarly, pathways found to be frequently upregulated in cancer patients,19, 20, 21 such as immune response and various signaling pathways, are either unaffected or show opposite trends in transduced CD34+ cells compared with AML blasts. Hence in conclusion, the pathway-centric analyses clearly demonstrate that AML blasts and oncogene-transduced CD34+ cells express distinct transcriptional programs.


Oncogenic fusion proteins expressed in immature hematopoietic cells fail to recapitulate the transcriptional changes observed in human AML.

Rapin N, Porse BT - Oncogenesis (2014)

Pathway-centric comparison of transcriptional changes in AML blasts and CD34+ cells transduced with the same oncogenes. Median gene-expression fold change of selected MsigDB gene signatures that are significantly (P<1e−5) enriched among genes found to be deregulated in AML blasts samples. Fold change is computed relative to controls for transduced cells, and relative to the closest normal counterpart for AMLs blasts.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150216&req=5

fig2: Pathway-centric comparison of transcriptional changes in AML blasts and CD34+ cells transduced with the same oncogenes. Median gene-expression fold change of selected MsigDB gene signatures that are significantly (P<1e−5) enriched among genes found to be deregulated in AML blasts samples. Fold change is computed relative to controls for transduced cells, and relative to the closest normal counterpart for AMLs blasts.
Mentions: Finally, we took a pathway-centric approach to compare the transcriptional changes in AML blasts with those in transduced CD34+ cells. Specifically, we first identified gene signatures found to be significantly (P<1e−5, hypergeometric test) deregulated in AML blasts versus normal cells.16 We next report their median fold changes, relative to control and nearest normal counterparts, in transduced CD34+ cells and in a subset of AML blast samples, respectively (Figure 2). Strikingly, while gene signatures associated with cell cycle processes are generally downregulated in AML blasts, we note that the transduced CD34+ cells only exhibit a transient downregulation of these pathways. Such behavior could potentially be associated with an adaptation to the culture conditions. Similarly, pathways found to be frequently upregulated in cancer patients,19, 20, 21 such as immune response and various signaling pathways, are either unaffected or show opposite trends in transduced CD34+ cells compared with AML blasts. Hence in conclusion, the pathway-centric analyses clearly demonstrate that AML blasts and oncogene-transduced CD34+ cells express distinct transcriptional programs.

Bottom Line: Here, we critically assessed the potential of such in vitro models using an integrative bioinformatics approach.Surprisingly, we found that the gene-expression profiles of CD34+ human HSPCs transformed with the potent oncogenic fusion proteins AML-ETO or MLL-AF9, only weakly resembled those derived from primary AML samples.Hence, our work raises concerns as to the relevance of the use of in vitro transduced cells to study the impact of transcriptional deregulation in human AML.

View Article: PubMed Central - PubMed

Affiliation: 1] The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark [2] Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark [3] Department of Biology, Faculty of Natural Sciences, The Bioinformatics Centre, University of Copenhagen, Copenhagen, Denmark [4] Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

ABSTRACT
Reciprocal chromosomal translocations are observed in one-third of acute myeloid leukemia (AML) cases. Targeting and understanding the effects of the resulting aberrant oncogenic fusion proteins may help developing drugs against specific leukemic subtypes, as demonstrated earlier by the use of ATRA in acute promyelocytic leukemia. Hematopoietic stem/progenitor (HSPCs) cells transduced with oncogenic fusion genes are regarded as promising in vitromodels of their corresponding AML subtypes. Here, we critically assessed the potential of such in vitro models using an integrative bioinformatics approach. Surprisingly, we found that the gene-expression profiles of CD34+ human HSPCs transformed with the potent oncogenic fusion proteins AML-ETO or MLL-AF9, only weakly resembled those derived from primary AML samples. Hence, our work raises concerns as to the relevance of the use of in vitro transduced cells to study the impact of transcriptional deregulation in human AML.

No MeSH data available.


Related in: MedlinePlus