GENETIC ANALYSIS OF MYELOPROLIFERATIVE DISEASE

Project: Research project

Project Details

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.
StatusFinished
Effective start/end date4/1/992/28/19

ASJC

  • Medicine(all)