An Erythroid Differentiation Signature Predicts Response to Lenalidomide in Myelodysplastic Syndrome

Ebert, Benjamin L.; Galili, Naomi; Tamayo, Pablo; Bosco, J.; Mak, Raymond H.; Pretz, Jennifer; Tanguturi, Shyam; Ladd‐Acosta, Christine; Stone, Richard; Golub, Todd R.; Raza, Azra

doi:10.1371/journal.pmed.0050035

Cited by 150 publications

(107 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…28 Lenalidomide has many biologic activities, including the promotion of erythropoiesis, modulation of cytokine production, inhibition of 2 phosphatases on 5q (CDC25C, and PP2A) and the activation of Rac1 and RhoA. [28][29][30][31][32] RPS14 was identified as a 5qϪ syndrome gene in an RNA interference screen of each gene within the 5qϪ syndrome common deleted region. 3,33 In patients with the 5qϪ syndrome, 1 allele of RPS14 is deleted, 3 and haploinsufficient expression of RPS14 has been confirmed in patient samples.…”

Section: Q؊ Syndromementioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

698

726

View full text Add to dashboard Cite

Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, SchwachmanDiamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q؊ syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. Identification of ribosomal abnormalities in human diseaseIn 1999, Draptchinskaia et al reported recurrent mutations in a ribosomal protein gene, RPS19, in patients with Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure syndrome with a striking erythroid defect. 1 Since that initial discovery, mutations in a number of ribosomal proteins have been identified in up to 50% of patients with DBA. Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects. The disorders of ribosome dysfunction have become collectively known as ribosomopathies. Overview of ribosome biogenesisThe eukaryotic ribosome is composed of 40S and 60S subunits, which associate to form the translationally active 80S ribosome. This process requires the coordinated synthesis of 4 ribosomal RNAs (rRNAs), approximately 80 core ribosomal proteins, more than 150 associated proteins, and approximately 70 small nucleolar RNAs (snoRNAs). 4,5 The 40S subunit contains 18S rRNA and the 60S subunit contains 28S, 5.8S, and 5S rRNAs. In eukaryotes, assembly of rRNA and ribosomal proteins, along with assoc...

show abstract

Section: Q؊ Syndromementioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

698

726

View full text Add to dashboard Cite

show abstract

“…49 Response to lenalidomide, another hallmark of 5q deletions in MDS, may be due to the severity of the block in erythroid differentiation, and the ability of lenalidomide to induce erythroid differentiation. 50 Lenalidomide causes selective apoptosis of 5q-deleted cells associated with a G 2 cell cycle arrest. Two phosphatases on 5q, CDC25C and PP2A regulate the cell cycle, and expression of both genes is decreased in cells with 5q deletions.…”

Section: Identifcation Of Other Candidate Genes On 5qmentioning

confidence: 99%

Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancer

Ebert

2009

Leukemia

View full text Add to dashboard Cite

“…A gene known as SPARC has been associated with response to lenalidomide, 58 as well as a set of genes in an erythroid response pathway. 59 A phosphatase has also been shown to be involved with the activity of lenalidomide. 60 With the exception of lenalidomide and del5q, there are very few predictive biomarkers of response to therapy in MDS.…”

Section: Molecular Markers Of Response To Therapymentioning

confidence: 99%

Prognosis of Myelodysplastic Syndromes

Garcia-Manero

2010

Hematology

View full text Add to dashboard Cite

The myelodysplastic syndromes (MDS) are a very complex group of hematopoietic disorders. The degree of complexity relates not only to the intrinsic pathobiological characteristics of the disease, but also to the group of patients whom it affects most frequently: older individuals or those who have been exposed to prior forms of chemotherapy. It is therefore crucial to develop clinical tools to predict with a certain degree of precision the prognosis and outcome for patients with specific subtypes of MDS in specific clinical situations. At the present time, patients with MDS are diagnosed using a set of well-established histopathological criteria. Prognosis is established using classifications that include morphological features, percentage of blasts, and clinical and molecular characteristics such as peripheral cytopenias and cytogenetics. The International Prognostic Scoring System (IPSS) is a classic example of this type of classification. Over the last 5 years, there has been an intense effort to develop new prognostic systems for MDS, and new molecular alterations with potential prognostic value have been discovered. Over the same period of time, several new therapeutic interventions have been developed for patients with MDS. Biomarkers of response to these agents, in particular for the hypomethylating agents, are needed to predict clinical benefit. This review summarizes current prognostic models of MDS and new molecular alterations with potential prognostic potential.

show abstract

An Erythroid Differentiation Signature Predicts Response to Lenalidomide in Myelodysplastic Syndrome

Cited by 150 publications

References 32 publications

Ribosomopathies: human disorders of ribosome dysfunction

Ribosomopathies: human disorders of ribosome dysfunction

Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancer

Prognosis of Myelodysplastic Syndromes

Contact Info

Product

Resources

About