TELOMERES AND TELOMERASE IN MYELOMA AND MDS

University Of Arkansas Med Scis Ltl Rock, Little Rock AR

Investigators

Linked publications & trials

Abstract

DESCRIPTION: (Applicant's Description) Myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML) occur with disconcerting frequency in myeloma patients following high-dose chemotherapy and autologous stem cell transplantation. In prospective and retrospective studies, we will evaluate several risk factors for these disorders. These include the nature of alkylating therapy, age, genetic predisposition, immunosuppression, antiangiogenesis therapy, and proliferative senescence within the hematopoietic system. Cytogenetic instability, involving short telomeres and chromosome end-fusion, associated with proliferative senescence is seen in telomerase knockout mice. Leukocyte telomere length will be measured serially to correlate progressive telomere shortening, stem cell destruction and development of aneuploidy and MDS. Qualitative and quantitative measures of the CD34+ population in patient marrow and mobilized peripheral blood will involve in vitro clonogenic assays, long-term stromal cell co-culture, and cytokine-driven serial expansion cultures. Stem-cell function will be further assessed using transendothelial chemotaxis assays, TRAP assay for telomerase levels, and NOD/SCID transplantation. These parameters, including evidence of proliferation and/or maturation defects associated with MDS, will be correlated with cytogenetic evaluation by G-banding and interphase fluorescence in situ hybridization (FISH). The study groups include patients on Total Therapy II and previously treated patients to determine whether autograft-supported, high-dose melphalan has a higher leukemogenic potential than DT-PACE. Increased telomerase levels are associated either with myeloma or MDS/AML, in order to overcome telomere shortening and proliferative senescence. We shall evaluate telomerase levels throughout therapy, to determine the prognostic and diagnostic value of this parameter, in conjunction with other features such as telomere length, cytogenetic status, and proliferative rate. Our observation of a therapyrelated "MDS/leukemic signature" among myeloma cells exhibiting a "myeloma signature" suggests a common evolutionary pathway progressing toward malignancy in both the plasma cell and myeloid lineage. The role of therapy, telomere shortening and telomerase activity will be assessed with respect to this phenomenon. We will also develop a retroviral gene-transduction strategy for high expression of the human telomerase catalytic component in senescing CD34+ cells with short telomeres to explore this approach for telomere elongation and stem-cell rejuvenation.