Dr. Benjamin Braun
is investigating myeloid
malignanices which are caused by abnormal proliferation, differentiation
and survival of hematopoietic progenitors. Which of these processes is
aberrant, and to what degree, determines the
properties of each disease. Acute myeloid leukemia (AML) is
characterized by rapid proliferation of immature blast cells,
myeloproliferative disorders (MPDs) involve a more indolent
accumulation of mature myeloid cells, and myelodysplastic syndromes
(MDS) involve aberrant and inefficient differentiation and reduced
blood cell counts.
Despite this diversity, these disorders share several phenotypic and
genetic similarities. Most importantly, these disorders generally carry
a poor prognosis despite maximally intensive therapy. With respect to
cell biology, are characterized by dominance
of hematopoiesis by an abnormal clone. Finally, some genetic mutations
are commonly found in the entire family of myeloid neoplasms. For example,
activating RAS mutations are found in about one third of cases of childhood
AML, MPD and MDS. Normal RAS genes encode small GTPases that mediate signals
from the external environment that are sensed by transmembrane receptors.
Ras proteins cycle between inactive, GDP-bound and active, GTP-bound forms,
which regulation by activating guanine nucleotide exchange factors (GEFs)
and GTPase activating proteins (GAPs). Cancer-associated RAS alleles encode
proteins that strongly favor the active, GTP-bound state by inhibiting
both innate and GAP-stimulated GTPase activity. The cellular response
to Ras signaling depends on cell type and may involve proliferation, survival
and/or differentiation. A positive role in growth is suggested by the
frequency (~20%) with which RAS genes are mutated in human cancer. A specific
role for promoting myeloid leukemia is further supported by findings that
most cases of AML or MPD without RAS mutations involve
the pathway by mutation of upstream activators of Ras, such as expression
of the Bcr-Abl tyrosine kinase in CML, or loss of the GAP protein neurofibromin
in JMML. We have investigated the role of mutant RAS alleles in myeloid
cell fate by generating an accurate genetic model of somatic mutation
of the Kras gene using a conditional knock-in allele. When the oncogenic
allele is expressed from the endogenous locus in hematopoietic stem cells,
mice rapidly and uniformly develop a MPD closely modeling human JMML and
CMML. We are now harnessing this system to study the biochemical and cell
biologic abnormalities caused by mutant RAS in these mice. We also are
building systems for
preclinical evaluation of potential therapeutic agents using a combination
of in vitro and in vivo assays.
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