Relationship of differential gene expression profiles in CD34+ myelodysplastic syndrome marrow cells to disease subtype and progression

Sridhar, Kunju; Ross, Douglas T.; Tibshirani, Robert; Butte, Atul J.; Greenberg, Peter L.

doi:10.1182/blood-2009-08-236422

Cited by 67 publications

(70 citation statements)

References 50 publications

(62 reference statements)

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“…In addition, recent molecular studies have indicated that both single gene mutations (e.g. oncogenes, cell cycle regulators, transcription factors) (Table II) (Davis & Greenberg, 1998;Parker et al, 2000;Greenberg, 2006a;Czibere et al, 2009;Kosmider et al, 2009) and global differential expression profiles of genes from marrow cells (Mills et al, 2009;Sridhar et al, 2009) have major prognostic value.…”

Section: Mds Classificationsmentioning

confidence: 99%

Current therapeutic approaches for patients with myelodysplastic syndromes

Greenberg

2010

Br J Haematol

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SummaryThe myelodysplastic syndromes (MDS) are a heterogeneous spectrum of disorders requiring selective therapy based on patients' specific clinical features, predominantly their prognostic subgroups, age and performance status. Guidelines for management of patients with MDS have been generated by a number of national panels. This review focuses on evidencebased data supporting therapeutic approaches, which have also been recommended by the US National Comprehensive Cancer Network MDS Panel, with discussion of accessibility of recommended drugs in the US and in other countries. For lower risk disease (International Prognostic Scoring System Low and Intermediate-1) therapy is aimed at haematological improvement whereas for higher risk disease (Intermediate-2 and High) treatment focuses on altering disease natural history. Recent information regarding additional clinical and biological features has provided useful parameters for assessing disease prognosis that aid risk-based management decisions. The rationale for use of low versus high intensity therapies with these agents, including allogeneic haematopoietic stem cell transplantation, is discussed in detail.

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Section: Mds Classificationsmentioning

confidence: 99%

Current therapeutic approaches for patients with myelodysplastic syndromes

Greenberg

2010

Br J Haematol

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“…These proteins are all important in cellular iron acquisition (and therefore are critical for erythroid differentiation) and may play pivotal roles in MDS and AML. Furthermore, global gene expression profiling has shown that the expression of target genes of c-Myc differs significantly between MDS patients and normal subjects (21,22). These observations suggest a potential key role for c-Myc in MDS.…”

Section: Myelodysplastic Syndromes (Mds)mentioning

confidence: 92%

5-Aza-2′-deoxycytidine Activates Iron Uptake and Heme Biosynthesis by Increasing c-Myc Nuclear Localization and Binding to the E-boxes of Transferrin Receptor 1 (TfR1) and Ferrochelatase (Fech) Genes

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Liu

et al. 2011

Journal of Biological Chemistry

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The hypomethylating agent 5-aza-2-deoxycytidine (5-aza-CdR) and its derivatives have been successfully used for the treatment of myelodysplastic syndromes, and they frequently improve the anemia that usually accompanies these disorders. However, the molecular mechanisms underlying this action remain poorly understood. In this study, we used two erythroid models, murine erythroid leukemia cells and erythroid burst-forming unit-derived erythroblasts, to show that 5-aza-CdR induced erythroid differentiation and increased the expression of transferrin receptor 1 (TfR1) and ferrochelatase (Fech), thereby increasing iron uptake and heme biosynthesis. We have identified new regulatory E-boxes that lie outside of CpG islands in the TfR1 and Fech promoters, and the methylation status of these sites can be altered by 5-aza-CdR treatment. This in turn altered the binding of the transcription factor c-Myc to these promoter elements. Furthermore, 5-aza-CdR promoted the nuclear translocation of c-Myc and its binding to Max to form functional complexes. The coordinated actions of 5-aza-CdR on the methylation status of the target genes and in stimulating the nuclear translocation of c-Myc provide new molecular insights into the regulation of E-boxes and explain, at least in part, the increased erythroid response to 5-aza-CdR treatment.

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“…37,38 These abnormalities involve genes engaged in molecular signaling and differentiation, regulation of cell cycle progression, apoptosis, transcription, translation, and epigenetics (Table 1). Investigations using next-generation DNA sequencing technology showed a substantial number of somatic gene mutations in marrow from patients with MDS.…”

Section: Prognostic Molecular Abnormalitiesmentioning

confidence: 99%

“…35,36 Prognostic Molecular Abnormalities Molecular investigations have indicated that both single-gene mutations and global differential expression profiles of genes from marrow cells have major prognostic value. 37,38 These abnormalities involve genes engaged in molecular signaling and differentiation, regulation of cell cycle progression, apoptosis, transcription, translation, and epigenetics (Table 1).…”

Section: Molecular Featuresmentioning

confidence: 99%

“…Using microarray techniques, distinctive gene expression profiles (GEPs) with poorrisk gene expression signatures of MDS marrow CD34 + cells were shown in patients whose disease transformed to AML within a relatively short time (ie, 14 months) compared with those with stable disease. 37 Other GEP studies have shown prognostic import for MDS. 38 Among the most significantly deregulated gene pathways in early MDS were immunodeficiency, apoptosis, and chemokine signaling, whereas advanced MDS was characterized by deregulation of DNA damage response and checkpoint pathways.…”

Section: Gene Expression Deregulationmentioning

confidence: 99%

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The Multifaceted Nature of Myelodysplastic Syndromes: Clinical, Molecular, and Biological Prognostic Features

Greenberg

2013

J Natl Compr Canc Netw

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The myelodysplastic syndromes (MDS) consist of a heterogeneous spectrum of myeloid clonal hemopathies. The Revised International Prognostic Scoring System (IPSS-R) provides a recently refined method for clinically evaluating the prognosis of patients with MDS. Molecular profiling has recently generated extensive data describing critical hematopoietic molecular and biologic derangements contributing to clinical phenotypes. Current molecular insights have demonstrated roles of specific somatic gene mutations in the development and clinical outcomes of MDS, including their propensity to progress to more aggressive stages, such as acute myeloid leukemia. This article focuses on these recently reported clinical and underlying pathogenetic findings. The discussion provides a synthesis of the prognostic clinical, molecular, and biologic abnormalities intrinsic to the aberrant marrow hematopoietic and microenvironmental influences in MDS. (JNCCN 2013;11:877-885) NCCN: Continuing Education Accreditation StatementThis activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center`s Commission on Accreditation.This activity is accredited for 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 70% minimum passing score and complete the evaluation at http://education.nccn.org/ node/23880; and 4) view/print certificate.Release date: July 12, 2013; Expiration date: July 12, 2014 Learning ObjectivesUpon completion of this activity, participants will be able to:• Clinical Features Prognostic CharacterizationThe International Prognostic Scoring System (IPSS) has been an important standard for assessing the prognosis of adult patients with untreated primary MDS.1 However, since its publication in 1997, additional prognostic systems have been suggested providing other parameters to indicate meaningful differences in clinical outcomes, 2-5 and the WHO hematopathologists added a morphologic refinem...

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Relationship of differential gene expression profiles in CD34+ myelodysplastic syndrome marrow cells to disease subtype and progression

Cited by 67 publications

References 50 publications

Current therapeutic approaches for patients with myelodysplastic syndromes

Current therapeutic approaches for patients with myelodysplastic syndromes

5-Aza-2′-deoxycytidine Activates Iron Uptake and Heme Biosynthesis by Increasing c-Myc Nuclear Localization and Binding to the E-boxes of Transferrin Receptor 1 (TfR1) and Ferrochelatase (Fech) Genes

The Multifaceted Nature of Myelodysplastic Syndromes: Clinical, Molecular, and Biological Prognostic Features

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