Myelodysplastic syndrome (MDS) is an acquired bone marrow disorder characterized by dysplastic growth of hematopoietic progenitors, peripheral cytopenia, and progression to acute myelogenous leukemia (AML). It can be viewed as a transition state between normal hematopoiesis and AML, and is loosely analogous to intermediate states in other models of tumor progression (e.g., adenomas in pathogenesis of colon cancer). The molecular basis for MDS is unknown. The importance of understanding pathogenesis of this disorder is heightened by lack of effective therapy apart from bone marrow transplantation.
The specific aims of this proposal are to (i) determine clonal involvement of hematopoietic lineages in MDS. Identification of somatic mutation which causes MDS requires analysis of clonally derived cells. Since cells are limiting in pancytopenic MDS patients, polymerase chain reaction (PCR) will be used to determine clonality. The method will be applied to clonal analysis of MDS, and other acquired bone marrow disorders where cell number has limited clonality analysis (e.g., aplastic anemia). (ii) determine whether homozygous deletion is responsible for pathogenesis of 5q- syndrome. 5q- is the most common chromosomal abnormality associated with MDS. Homozygous deletion of a gene on 5q has been proposed as a mechanism for disease pathogenesis in these patients. Clonally derived cells from patients with 5q- deletion will be analyzed for evidence of homozygous deletion. Analysis will include Southern blots using probes for known genes and for anonymous loci on 5q, analysis of expression of candidate 5q genes using competitive PCR, and amplification and direct sequence analysis of selected regions of candidate genes on 5q such as EGR-1. (iii) identify the genetic locus in a large kindred responsible for autosomal dominant inheritance of a functional platelet defect and strong propensity to develop AML. Affected family members in this kindred have a dysfunctional platelet syndrome, detectable at birth, that has similarities to that seen in MDS. Further, affected family members have a strong tendency to develop AML. In one patient for whom karyotype data is available, a 5q- and 11q- deletion was associated with progression to AML. The family thus provides an unusual opportunity to identify a genetic locus which causes a preleukemic dysfunctional platelet syndrome, and is associated with chromosomal abnormalities frequently seen in MDS. The locus will be identified by linkage analysis using cosmid probes for polymorphic loci on 5q and 11q, and will be expanded to other chromosomes if these regions are not informative.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA057261-04
Application #
2098013
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1992-04-01
Project End
1996-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Golub, T R; Goga, A; Barker, G F et al. (1996) Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. Mol Cell Biol 16:4107-16
Hiebert, S W; Sun, W; Davis, J N et al. (1996) The t(12;21) translocation converts AML-1B from an activator to a repressor of transcription. Mol Cell Biol 16:1349-55
Stegmaier, K; Takeuchi, S; Golub, T R et al. (1996) Mutational analysis of the candidate tumor suppressor genes TEL and KIP1 in childhood acute lymphoblastic leukemia. Cancer Res 56:1413-7
McLean, T W; Ringold, S; Neuberg, D et al. (1996) TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia. Blood 88:4252-8
Sato, Y; Suto, Y; Pietenpol, J et al. (1995) TEL and KIP1 define the smallest region of deletions on 12p13 in hematopoietic malignancies. Blood 86:1525-33
Stegmaier, K; Pendse, S; Barker, G F et al. (1995) Frequent loss of heterozygosity at the TEL gene locus in acute lymphoblastic leukemia of childhood. Blood 86:38-44
Golub, T R; Barker, G F; Lovett, M et al. (1994) Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 77:307-16
Busque, L; Ilaria Jr, R; Tantravahi, R et al. (1994) Clonality analysis of childhood ALL in remission: no evidence of clonal hematopoiesis. Leuk Res 18:71-7
Abhyankar, S; Gilliland, D G; Ferrara, J L (1993) Interleukin-1 is a critical effector molecule during cytokine dysregulation in graft versus host disease to minor histocompatibility antigens. Transplantation 56:1518-23
Busque, L; Gilliland, D G (1993) Clonal evolution in acute myeloid leukemia. Blood 82:337-42