The Role of Erythropoietin in Myelodysplastic Syndrome

The purpose of the study is to elucidate the causative molecular events responsible for the abnormal erythropoiesis in MDS.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndrome

Detailed Description

Myelodysplastic syndromes are a heterogeneous group of disorders characterized by clonal expansion of hematopoietic stem cells and ineffective hematopoiesis. Although all 3 cell lineages in myeloid hematopoiesis can be involved, the erythroid dysplasia and ineffective erythropoiesis of MDS are usually the most severe, and often precede the development of other bone marrow lineage defects.

In normal erythropoiesis, erythroid progenitors differentiate and proliferate in response to stimulation by erythropoietin (Epo). Epo binds to its receptor, EpoR, constitutively expressed at the surface of committed erythroid progenitors and induces homodimerization. This study is designed to evaluate the EpoR cDNA sequence and its level of expression in the clonal erythroid progenitors of MDS patients (in cells stratified for the same degree of erythroid maturation) to determine whether mutations in the EpoR may be responsible for an aberrant Epo signal transduction in MDS. As well as analyze intrinsic erythroid Epo expression to determine whether it differs between normal controls and patients with MDS and perform a microarray analysis of genes associated with Epo signal transduction to determine if MDS patients have abnormal expression of signal transduction proteins.

• Study Type: Observational
• Enrollment (Actual): 8

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
    • Salt lake City, Utah, United States, 84148
      • VA Salt Lake City Health Care System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Subjects diagnosed with myelodysplastic syndrome

Description

Inclusion Criteria:

• Adult subjects greater than 18 years of age
• Diagnosis of MDS based on the French-American-British classification system (including secondary causes of MDS)

Exclusion Criteria:

• Subjects not meeting the criteria listed above

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Affected Group; Adult subjects with the diagnosis of MDS based on the French-American-British classification system.
Healthy Controls; Control subjects will be selected using frequency matching on gender and age by decade. That is for each MDS patient a healthy volunteer of the same gender and decade (50-59, 60-69, 70-79, etc) will be selected

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Evaluate the EpoR cDNA sequence and its level of expression in the clonal erythroid progenitors of MDS patients to determine whether mutations in the EpoR may be responsible for an aberrant Epo signal transduction in MDS.	After Samples are obtained

Secondary Outcome Measures

Outcome Measure	Time Frame
Analyze intrinsic erythroid Epo expression to determine whether it differs between normal controls and patients with MDS.	After samples are obtained
Perform a microarray analysis of genes associated with Epo signal transduction to determine if MDS patients have abnormal expression of signal transduction proteins.	After samples are obtained
Determine how often and what percent clonality occurs in MDS patients and try to predict who has early MDS by clonality testing.	After samples from female patients have been obtained

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: National Institutes of Health (NIH)

Publications and helpful links

General Publications

• Aul C, Arning M, Runde V, Schneider W. Serum erythropoietin concentrations in patients with myelodysplastic syndromes. Leuk Res. 1991;15(7):571-5. doi: 10.1016/0145-2126(91)90025-o.
• Stasi R, Brunetti M, Terzoli E, Abruzzese E, Amadori S. Once-weekly dosing of recombinant human erythropoietin alpha in patients with myelodysplastic syndromes unresponsive to conventional dosing. Ann Oncol. 2004 Nov;15(11):1684-90. doi: 10.1093/annonc/mdh428.
• Casadevall N, Durieux P, Dubois S, Hemery F, Lepage E, Quarre MC, Damaj G, Giraudier S, Guerci A, Laurent G, Dombret H, Chomienne C, Ribrag V, Stamatoullas A, Marie JP, Vekhoff A, Maloisel F, Navarro R, Dreyfus F, Fenaux P. Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial. Blood. 2004 Jul 15;104(2):321-7. doi: 10.1182/blood-2003-07-2252. Epub 2004 Mar 30.
• Solignac M; European Hematology Association. [Epoetin beta, new strategies to optimise the management of anaemia in cancer patients]. Presse Med. 2003 Sep 13;32(29):1385-8. No abstract available. French.
• Fontenay-Roupie M, Bouscary D, Guesnu M, Picard F, Melle J, Lacombe C, Gisselbrecht S, Mayeux P, Dreyfus F. Ineffective erythropoiesis in myelodysplastic syndromes: correlation with Fas expression but not with lack of erythropoietin receptor signal transduction. Br J Haematol. 1999 Aug;106(2):464-73. doi: 10.1046/j.1365-2141.1999.01539.x.
• Takeshita A, Shinjo K, Naito K, Ohnishi K, Higuchi M, Ohno R. Erythropoietin receptor in myelodysplastic syndrome and leukemia. Leuk Lymphoma. 2002 Feb;43(2):261-4. doi: 10.1080/10428190290006026.
• Shinjo K, Takeshita A, Higuchi M, Ohnishi K, Ohno R. Erythropoietin receptor expression on human bone marrow erythroid precursor cells by a newly-devised quantitative flow-cytometric assay. Br J Haematol. 1997 Mar;96(3):551-8. doi: 10.1046/j.1365-2141.1997.d01-2071.x.
• McMullin MF, Percy MJ. Erythropoietin receptor and hematological disease. Am J Hematol. 1999 Jan;60(1):55-60. doi: 10.1002/(sici)1096-8652(199901)60:13.0.co;2-v.
• Kralovics R, Sokol L, Broxson EH Jr, Prchal JT. The erythropoietin receptor gene is not linked with the polycythemia phenotype in a family with autosomal dominant primary polycythemia. Proc Assoc Am Physicians. 1997 Nov;109(6):580-5.
• Kralovics R, Indrak K, Stopka T, Berman BW, Prchal JF, Prchal JT. Two new EPO receptor mutations: truncated EPO receptors are most frequently associated with primary familial and congenital polycythemias. Blood. 1997 Sep 1;90(5):2057-61.
• Stopka T, Zivny JH, Stopkova P, Prchal JF, Prchal JT. Human hematopoietic progenitors express erythropoietin. Blood. 1998 May 15;91(10):3766-72.
• Sato TN. A new role of lipid receptors in vascular and cardiac morphogenesis. J Clin Invest. 2000 Oct;106(8):939-40. doi: 10.1172/JCI11304. No abstract available.

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (ACTUAL): October 1, 2010
• Study Completion (ACTUAL): October 1, 2010

Study Registration Dates

• First Submitted: July 24, 2008
• First Submitted That Met QC Criteria: July 25, 2008
• First Posted (ESTIMATE): July 28, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): November 23, 2010
• Last Update Submitted That Met QC Criteria: November 22, 2010
• Last Verified: November 1, 2010

More Information

Terms related to this study

• Keywords: Myelodysplastic Syndrome; Erythropoiesis; Ineffective Hematopoiesis; Erythroid Progenitors; Dyserythropoiesis
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia
• Other Study ID Numbers: 20716; DK007115-31