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Blood, 15 May 2001, Vol. 97, No. 10, pp. 3025-3031
HEMATOPOIESIS
Mimicry between neurokinin-1 and fibronectin may explain the
transport and stability of increased substance P
immunoreactivity in patients with bone marrow fibrosis
Pranela Rameshwar,
Deval D. Joshi,
Prem Yadav,
Jing Qian,
Pedro Gascon,
Victor T. Chang,
Devashish Anjaria,
Jonathan S. Harrison, and
Xiaosong Song
From the Departments of Medicine-Hematology/Oncology
and Surgery and the IST-Academic Computer Center, UMDNJ-New Jersey
Medical School, Newark, NJ.
Bone marrow (BM) fibrosis may occur in myeloproliferative diseases,
lymphoma, myelodysplastic syndrome, myeloma, and infectious diseases.
In this study, the role of substance P (SP), a peptide with pleiotropic
functions, was examined. Some of its functions angiogenesis, fibroblast proliferation, and stimulation of BM progenitorsare amenable to inducing BM fibrosis. Indeed, a significant increase was
found in SP-immunoreactivity (SP-IR) in the sera of patients with BM
fibrosis (n = 44) compared with the sera of patients with hematologic
disorders and no histologic evidence of fibrosis (n = 46) (140 ±12
vs 18 ±3; P < .01). Immunoprecipitation of sera SP
indicated that this peptide exists in the form of a complex with other
molecule(s). It was, therefore, hypothesized that SP might be complexed
with NK-1, its natural receptor, or with a molecule homologous to NK-1.
To address this, 3 cDNA libraries were screened that were constructed
from pooled BM stroma or mononuclear cells with an NK-1 cDNA probe. A
partial clone (clone 1) was retrieved that was 97% homologous to the
ED-A region of fibronectin (FN). Furthermore, sequence analyses
indicated that clone 1 shared significant homology with exon 5 of NK-1.
Immunoprecipitation and Western blot analysis indicated co-migration of
SP and FN in 27 of 31 patients with BM fibrosis. Computer-assisted
molecular modeling suggested that similar secondary structural features
between FN and NK-1 and the relative electrostatic charge might explain
a complex formed between FN (negative) and SP (positive). This study suggests that SP may be implicated in the pathophysiology of
myelofibrosis, though its role would have to be substantiated in
future research.
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