Abstract:Aberrations in protein ubiquitination have recently been identified in the pathogenesis of acute myeloid leukemia (AML). We studied whether expression changes of more than 1600 ubiquitination related genes correlated with clinical outcome in 525 adult AML patients. High expression of one of these genes, BRE, was observed in 3% of the cases and predicted favorable prognosis independently of known prognostic factors (5-year overall survival: 57%). Remarkably, unsupervised expression profiling showed that 86% of … Show more
“…To assess the potential clinical relevance of the cell of origin associated gene expression programs on the resulting leukemia we tested the correlation of expression of LG- and LH-signatures with clinical outcome in a group of 35 adult patients diagnosed with MLL -rearranged AML ( MLL -AML) for which two sets of microarray data were available (Bullinger et al, 2008; Noordermeer et al, 2011). 72 out of 121 LH-signature and 113 out of 162 LG-signature genes were present in the combined human dataset, which were then used to cluster samples.…”
Section: Resultsmentioning
confidence: 99%
“…Datasets were combined following the averaging of the expression of multiple clones/probesets measuring the same gene and the mean centering the cDNA and Affymetrix data in order to exclude platform specific effects. (Bullinger et al, 2008; Noordermeer et al, 2011). The raw data files will be available from Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/accession#GSE18483.FromGSE11889 (Bruns et al, 2009) we selected arrays for 5 normal HSC and GMP.…”
Summary
MLL-fusion proteins can induce acute myeloid leukemias (AML) from either hematopoietic stem cells (HSC) or granulocyte macrophage progenitors (GMP), but it remains unclear if the cell of origin influences the biology of the resultant leukemia. MLL-AF9 transduced single HSC or GMP could be continuously replated, but HSC-derived clones were more likely than GMP-derived clones to initiate AML in mice. Leukemia stem cells derived from either HSC or GMP had a similar immunophenotype consistent with a maturing myeloid cell (LGMP). Gene expression analyses demonstrated that LGMP inherited gene expression programs from the cell of origin including high-level Evi-1 expression in HSC derived LGMP. The gene expression signature of LGMP derived from HSC was enriched in poor prognosis human MLL-rearranged AML in three independent data sets. Moreover, global 5’-mC levels were elevated in HSC-derived leukemias as compared to GMP-derived leukemias. This mirrored a difference seen in 5-mC between MLL-rearranged human leukemias that are either EVI1-positive or EVI1-negative. Finally, HSC derived leukemias were more resistant to chemotherapy than GMP-derived leukemias. These data demonstrate that the cell of origin influences the gene expression profile, the epigenetic state, and the drug response in AML, and that these differences can account for clinical heterogeneity within a molecularly defined group of leukemias.
Significance
Human AMLs are heterogeneous even within subtype defined by a specific genetic lesion such as MLL-translocations and this leads to variable clinical outcomes. The developmental stage (or epigenetic state) of the cell in which leukemogenic transformation is initiated may contribute to the ultimate disease phenotype. We used a well established model of MLL-AF9 mediated AML and transformation of single cells to test the relevance of the leukemia cell of origin on AML development, gene expression profiles, DNA methylation and chemotherapy response. We show that HSC derived AML models human high-risk/poor outcome AML pool, and that we can recapitulate important clinical subtypes of human MLL-rearranged AML through the transformation of different cell types. These data demonstrate that the cell of origin can influence the phenotype of a resultant leukemia even if the initiating genetic lesion is the same.
“…To assess the potential clinical relevance of the cell of origin associated gene expression programs on the resulting leukemia we tested the correlation of expression of LG- and LH-signatures with clinical outcome in a group of 35 adult patients diagnosed with MLL -rearranged AML ( MLL -AML) for which two sets of microarray data were available (Bullinger et al, 2008; Noordermeer et al, 2011). 72 out of 121 LH-signature and 113 out of 162 LG-signature genes were present in the combined human dataset, which were then used to cluster samples.…”
Section: Resultsmentioning
confidence: 99%
“…Datasets were combined following the averaging of the expression of multiple clones/probesets measuring the same gene and the mean centering the cDNA and Affymetrix data in order to exclude platform specific effects. (Bullinger et al, 2008; Noordermeer et al, 2011). The raw data files will be available from Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/accession#GSE18483.FromGSE11889 (Bruns et al, 2009) we selected arrays for 5 normal HSC and GMP.…”
Summary
MLL-fusion proteins can induce acute myeloid leukemias (AML) from either hematopoietic stem cells (HSC) or granulocyte macrophage progenitors (GMP), but it remains unclear if the cell of origin influences the biology of the resultant leukemia. MLL-AF9 transduced single HSC or GMP could be continuously replated, but HSC-derived clones were more likely than GMP-derived clones to initiate AML in mice. Leukemia stem cells derived from either HSC or GMP had a similar immunophenotype consistent with a maturing myeloid cell (LGMP). Gene expression analyses demonstrated that LGMP inherited gene expression programs from the cell of origin including high-level Evi-1 expression in HSC derived LGMP. The gene expression signature of LGMP derived from HSC was enriched in poor prognosis human MLL-rearranged AML in three independent data sets. Moreover, global 5’-mC levels were elevated in HSC-derived leukemias as compared to GMP-derived leukemias. This mirrored a difference seen in 5-mC between MLL-rearranged human leukemias that are either EVI1-positive or EVI1-negative. Finally, HSC derived leukemias were more resistant to chemotherapy than GMP-derived leukemias. These data demonstrate that the cell of origin influences the gene expression profile, the epigenetic state, and the drug response in AML, and that these differences can account for clinical heterogeneity within a molecularly defined group of leukemias.
Significance
Human AMLs are heterogeneous even within subtype defined by a specific genetic lesion such as MLL-translocations and this leads to variable clinical outcomes. The developmental stage (or epigenetic state) of the cell in which leukemogenic transformation is initiated may contribute to the ultimate disease phenotype. We used a well established model of MLL-AF9 mediated AML and transformation of single cells to test the relevance of the leukemia cell of origin on AML development, gene expression profiles, DNA methylation and chemotherapy response. We show that HSC derived AML models human high-risk/poor outcome AML pool, and that we can recapitulate important clinical subtypes of human MLL-rearranged AML through the transformation of different cell types. These data demonstrate that the cell of origin can influence the phenotype of a resultant leukemia even if the initiating genetic lesion is the same.
“…In EVI1 neg MLL-rearranged leukemias, defects in other genes may have taken over this role. 26,39 We further investigated what could be the mechanism leading to up-regulation of Evi1 in a subset of MLL-AF9-transformed normal mBM cells. It is well established that the Evi1 locus contains a hot spot for retroviral insertions.…”
The proto-oncogene EVI1 (ecotropic viral integration site-1), located on chromosome band 3q26, is aberrantly expressed in human acute myeloid leukemia (AML) with 3q26 rearrangements.
“…1a). This is in contrast to AML in which BRE is highly expressed in a distinctive subset of patients, while the remaining patients show little variation [26]. Fig.…”
Section: Resultsmentioning
confidence: 93%
“…BRE expression was measured in both cohorts by QPCR using a commercially available primer/probe set (Hs01046283_m1, Life Technologies, Carlsbad, CA, USA) and normalized to expression of the housekeeping gene PBGD , as described in [26]. Normalized QPCR data were mean centered per analyzed cohort and afterward the data of the cohorts were combined to increase patient numbers for further analyses.…”
Breast cancer is one of the leading causes of cancer mortality in women. Recent advances in gene expression profiling have indicated that breast cancer is a heterogeneous disease and the current prognostication using clinico-pathological features is not sufficient to fully predict therapy response and disease outcome. In this retrospective study, we show that expression levels of BRE, which encodes a member of the BRCA1 DNA damage repair complex, predicted disease-free survival (DFS) in non-familial breast cancer patients. The predictive value of BRE expression depended on whether patients received radiotherapy as a part of their primary treatment. In radiotherapy-treated patients, high BRE expression predicted a favorable DFS (hazard ratio (HR) = 0.47, 95 % confidence interval (CI) = 0.28–0.78, p = 0.004), while in non-treated patients, high BRE expression predicted an adverse prognosis (HR = 2.59, 95 % CI = 1.00–6.75, p = 0.05). Among radiotherapy-treated patients, the prognostic impact of BRE expression was confined to patients with smaller tumors (HR = 0.23, 95 % CI = 0.068–0.75, p = 0.015) and it remained an independent factor after correction for the other prognostic factors age, tumor size, lymph node involvement, and histological grade (HR = 0.50, CI = 0.27–0.90, p = 0.021). In addition, high BRE expression predicted a favorable relapse-free survival in a publicly available dataset of 2,324 breast cancer patients (HR = 0.59, CI = 0.51–0.68, p < 0.001). These data indicate that BRE is an interesting candidate for future functional studies aimed at developing targeted therapies.
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