GENETIC ANALYSIS OF MYELOPROLIFERATIVE DISEASE

Project: Research projectResearch Project

Description

Myeloproliferative disorders (MPDs) result from the abnormal proliferation of myeloid precursor cells in the bone marrow. Understanding the genetic events which result in MPDs will not only improve our understanding of the disease process, but will also provide insights into the normal developmental control in early progenitor cells. A variant form of this disease is associated with T-cell leukemia/lymphoma and peripheral blood eosinophilia. The clinical course of the disease is particularly aggressive with rapid progression of the disease to acute myelogenous leukemia or stem cell leukemia. The involvement of both myeloid and T-cell lineages in this disease strongly suggest a primitive origin for the cells involved, before the commitment to a particular lineage. These tumors invariably show a highly specific, reciprocal chromosome translocation involving chromosomes 8 and 13. This specific translocation is always involved with this biphenotypic tumor indicating that genes located at the translocation breakpoints play an important role in disease development. The genes involved in this rearrangement have now been identified as FGFR1 in chromosome region 8p11 and a zinc finger gene, ZNF198, of unknown function, in 13q12. The molecular conequences of this rerrangement have been shown to be identical in all of the four cases we have analyzed. As a result of the rearrangement a fusion gene is generated which is under the control of the ZNF198 promoter. This novel gene carries the zinc finger motif of ZNF198 fused to the tyrosine kinase domain of FGFR1. Because of the highly specific nature of this rearrangement and its consistent presence in all of the tumors analyzed to date, this rearrangement must clearly be important in leukemogenesis in these patients. Our goals therefore are (1) to transform normal cells using the fusion gene in order to establish a functional assay in vitro, (2) to create a transgenic mouse line expressing the fusion protein and so establish an in vivo model to study the biological consequences of the translocation and (3) since the fusion gene may act as a dominant-negative we will also investigate the normal function of ZNF198 in order to compare its activity with that of the fusion gene. As a result of our improved understanding of the genetic events which give rise to this MPD, it may eventually be possible to design novel therapeutic approaches to this disease directed against the aberrant gene(s) and its product.
StatusActive
Effective start/end date4/1/992/28/19

Funding

  • National Institutes of Health: $256,058.00
  • National Institutes of Health: $286,425.00
  • National Institutes of Health: $108,831.00
  • National Institutes of Health: $277,833.00
  • National Institutes of Health: $307,125.00
  • National Institutes of Health: $322,746.00
  • National Institutes of Health: $286,425.00
  • National Institutes of Health
  • National Institutes of Health: $305,269.00
  • National Institutes of Health: $331,177.00
  • National Institutes of Health: $82,142.00
  • National Institutes of Health: $286,425.00
  • National Institutes of Health: $314,559.00
  • National Institutes of Health: $334,564.00

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Chromosomes
Leukemia
Myeloproliferative Disorders
Stem Cells
Neoplasms
Genes
Zinc Fingers
Receptor, Fibroblast Growth Factor, Type 1
Gene Fusion
Phosphotransferases
T-Cell Lymphoma
Cell Biology
Lymphoma
Myeloid Cells
Residual Neoplasm
Dimerization
Disease Management
Chromosome Aberrations
Bone Marrow Cells
Proteomics

Keywords

  • Medicine(all)