Blood, 15 August 2002, Vol. 100, No. 4, pp. 1109-1110
An animal model for myelofibrosis
Idiopathic myelofibrosis (IM) is an acquired,
insidious disorder characterized by collagen deposition in the bone
marrow, splenomegaly, and extramedullary hematopoiesis. Marrow
fibrosis, the hallmark histologic feature, is believed to represent a
reaction toward underlying clonal proliferation of hematopoietic cells. Indeed, progressive accumulation of some lineages, especially atypical
megakaryocytes, has long been recognized in IM, and other syndromes of
megakaryocyte hyperproliferation in man and mice are frequently
associated with secondary fibrosis. Although it is often assumed that
megakaryocyte products induce local collagen deposits, the molecular
basis of IM is unknown and is likely to be multifactorial. Moreover,
there is considerable heterogeneity in the extent and speed with which
myelofibrosis develops in response to diverse forms of megakaryocyte hyperplasia.
One mouse model of megakaryocytosis results from deficiency of the
transcription factor GATA1. Vannucchi and colleagues (page 1123) now
extend observations first hinted at by Takahashi et al (Blood.
1998;92:434-442) that, with age, GATA1-deficient mice develop a
clinical disorder that resembles IM. The phenotype is variably severe
and affected mice show no evidence for the most fearsome complication
of human IM, transformation to acute leukemia. This accurately reflects
the fundamental difference in underlying pathophysiology between the
human disease and the mouse model: the root cause of IM is clonal cell
proliferation, whereas GATA1-deficient mice principally model the late
sequelae, presumably, of nonclonal megakaryocyte excess. These findings
highlight the complex effects of GATA1 in regulating megakaryocyte
maturation, including the extracellular milieu associated with
incomplete differentiation.
Identifying the factors that drive collagen deposition in IM represents
an important challenge, and a genetically defined animal model could
prove invaluable in focused molecular studies. But the results reported
by Vannucchi et al suggest that many candidates may need to be
considered before the key molecular defects are known.
Regarding the question of pathogenic molecular lesions, it will
also be interesting to know whether and how acquired, clonal loss of
GATA1 function may contribute to a whole range of megakaryocyte
hyperplastic states.
Ramesh Shivdasani
Dana-Farber Cancer Institute; Harvard Medical
School
