Gene expression profiling in MDS and AML: potential and future avenues

Theilgaard‐Mönch, Kim; Boultwood, Jacqueline; Ferrari, Sérgio; Giannopoulos, Krzysztof; Hernández-Rivas, Jesús María; Kohlmann, Alexander; Morgan, Michael; Porse, Bo T.; Tagliafico, Enrico; Zwaan, C. Michel; Wainscoat, James S.; Heuvel‐Eibrink, Marry M. van den; Mills, Ken I.; Bullinger, Lars

doi:10.1038/leu.2011.48

Cited by 64 publications

(46 citation statements)

References 102 publications

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“…In vitro, one can demonstrate altered differentiation through clonogenic assays 3 and, in vivo, MDS cells have gene expression defects that are often in differentiation-related pathways. 4 Thus, while the characteristic bone marrow picture suggests abnormal proliferation (hypercellular marrow), the actual defect in MDS appears more traceable to abnormal differentiation, perhaps itself a trigger of compensatory proliferation. Indeed, a major difference between MDS and more classically proliferative neoplasms (such as acute myelogenous leukemia [AML]) is that myelodysplastic cells have a high rate of apoptosis, presumably as a result of the differentiation defects.…”

Section: Mds Is a Disease Of Disordered Differentiationmentioning

confidence: 99%

The myelodysplastic syndrome as a prototypical epigenetic disease

Issa

2013

Blood

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The myelodysplastic syndrome (MDS) is a clonal disorder characterized by increased stem cell proliferation coupled with aberrant differentiation resulting in a high rate of apoptosis and eventual symptoms related to bone marrow failure. Cellular differentiation is an epigenetic process that requires specific and highly ordered DNA methylation and histone modification programs. Aberrant differentiation in MDS can often be traced to abnormal DNA methylation (both gains and losses of DNA methylation genome wide and at specific loci) as well as mutations in genes that regulate epigenetic programs (TET2 and DNMT3a, both involved in DNA methylation control; EZH2 and ASXL1, both involved in histone methylation control). The epigenetic nature of MDS may explain in part the serendipitous observation that it is the disease most responsive to DNA methylation inhibitors; other epigenetic-acting drugs are being explored in MDS as well. Progression in MDS is characterized by further acquisition of epigenetic defects as well as mutations in growth-controlling genes that seem to tip the proliferation/apoptosis balance and result in the development of acute myelogenous leukemia. Although MDS is clinically and physiologically heterogeneous, a case can be made that subsets of the disease can be largely explained by disordered stem cell epigenetics.

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Section: Mds Is a Disease Of Disordered Differentiationmentioning

confidence: 99%

The myelodysplastic syndrome as a prototypical epigenetic disease

Issa

2013

Blood

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“…In cancer, GEP has been used successfully to identify cancer subtypes, to stratify patients into responders vs nonresponders, and to predict survival but has, to a large extent, failed to uncover genes that are causally involved in cancer initiation and maintenance. [1][2][3][4][5][6][7][8] These genes are obviously of great interest because they constitute potential targets for therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

Comparing cancer vs normal gene expression profiles identifies new disease entities and common transcriptional programs in AML patients

Rapin

Bagger

Jendholm

et al. 2014

Blood

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“…[6][7][8][9] However, specific genes that contribute to MDS progression are still not completely understood. 10 Deregulation of programmed cell death contributes to leukemogenesis and to blast cell survival. Cells resistant to apoptosis are prone to accumulate genetic aberrations, acquire the capacity to survive independently from growth factor stimulation and escape from immune system control.…”

Section: Introductionmentioning

confidence: 99%