Bone marrow-specific protein

Details Bone marrow-specific protein Bone marrow-specific protein

2000-01-13

2003-03-18

Park, Hankyel T. (Department: 1648)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C530S350000, C435S320100, C435S325000, C435S455000, C424S184100, C424S185100

Reexamination Certificate

active

06534485

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel human gene encoding a polypeptide which is a member of the erythroid differentiation factor family. More specifically, the present invention relates to a polynucleotide encoding a novel human polypeptide named Bone Marrow-Specific Protein, or “BMSP.” This invention also relates to BMSP polypeptides, as well as vectors, host cells, antibodies directed to BMSP polypeptides, and the recombinant methods for producing the same. Also provided are diagnostic methods for detecting disorders related to the immune system, and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying agonists and antagonists of BMSP activity.
BACKGROUND OF THE INVENTION
Erythroid cells are critically important for embryonic development. During embryonic development, two distinct forms of erythropoiesis occur. First, a ‘primitive’ form consists of nucleated erythroblasts that differentiate within the blood vessels of the extraembryonic yolk sac. Second, a ‘definitive’ form consists of anucleate erythrocytes that differentiate within the liver and third trimester bone marrow of the fetus. During the third trimester the fetus grows rapidly and the production of red cells is approximately 3-5 times that of adult steady state levels. Erythropoiesis occurs first in the yolk sac, subsequently in the liver, and then the bone marrow and, in rodents, the spleen during development. Birth brings dramatic changes in oxygenation and erythropoietin production that result in a tenfold drop in red cell production and in a transient ‘physiologic’ anemia. Even in the adult, vestiges of fetal erythropoiesis are evident during transient states of accelerated erythroid expansion. The precise complement of molecular factors and signals which mediate the processes involved in erythropoiesis and developmental progression of other immune cells both during fetal development and after birth is not clearly defined.
Myeloid cells arise from a common stem cell progenitor whose development is regulated by stimulatory and inhibitory growth factors. Pluripotential hematopoietic stem cells are most influenced by cytokines and growth factors including, but not limited to, IL-3, GM-CSF, and stem cell factor while committed progenitor cells are regulated by variable concentrations of cytokines and growth factors including, for example, GM-CSF, G-CSF, M-CSF, IL-5, Epo, and Tpo. Both dysplastic and neoplastic conditions can thus be traced to a common origin. Dysplastic changes may signal early neoplastic changes with cases progressing to acute leukemia. Myelodysplastic syndrome (MDS) is associated with anemia or multiple cytopenias, normal to hypercellular bone marrow, ineffective hematopoiesis, and less than 30% blast cells of all nucleated cells in the bone marrow. Chronic myeloid leukemias also have less than 30% blast cells of all nucleated cells in the bone marrow and are distinguished from MDS by elevated cell counts of one or more cell lines with mature forms predominating. Acute myeloid leukemias, often the end result of all myeloproliferative disorders, are recognized by equal or greater 30% blast cells of all nucleated cells in the bone marrow. In fact, although many myelogenic regulatory factors have been at least preliminarily characterized, it is clear that a number of factors have not yet been identified.
Thus, there is a need for polypeptides that are involved in bone growth defects and immune functions, such as defects in stem cell growth and/or blood cell differentiation, since disturbances of such regulation may be involved in disorders relating to immune system. Therefore, there is a need for identification and characterization of such human polypeptides which can play a role in detecting, preventing, ameliorating or correcting such disorders.
SUMMARY OF THE INVENTION
The present invention relates to a novel polynucleotide and the encoded polypeptide of BMSP. Moreover, the present invention relates to vectors, host cells, antibodies, and recombinant methods for producing the polypeptides and polynucleotides. Also provided are diagnostic methods for detecting disorders relates to the polypeptides, and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying binding partners of BMSP.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1
shows the nucleotide sequence (SEQ ID NO:1) and the deduced amino acid sequence (SEQ ID NO:2) of BMSP. Two potential Casein Kinase II (CK2) phosphorylation sites are marked in
FIG. 1
with bolded serine (S) or threonine (T) symbols in the BMSP amino acid sequence and also marked with an asterisk (*) above the first nucleotide encoding the appropriate serine and threonine residues in the BMSP nucleotide sequence. The first potential CK2 phosphorylation sequence is found at the following location in the BMSP amino acid sequence: S-33 through D-36 (S-33, E-34, E-35, and D-36). The second potential CK2 phosphorylation sequence is found at the following location in the BMSP amino acid sequence: T-39 through E42 (T-39, V-40, V-41, and E-42).
Regions of high identity between BMSP and the closely related Mus musculus erythroid differentiation related factor (MEDRF) sequence (SEQ ID NO:3) are delineated in
FIG. 1
with a double underline. These regions are not limiting and are labeled as Conserved Domain (CD)-I, CD-II, CD-III, CD-IV, CD-V, CD-VI, and CD-VII in FIG.
1
.
FIG. 2
shows the regions of identity between the amino acid sequence of the BMSP protein and the translation product of the Mus musculus erythroid differentiation related factor (MEDRF) gene (SEQ ID NO:3; ATCC Accession No. AF060220), determined by BLAST analysis. By examining the regions of amino acids which are identical or similar between BMSP and MEDRF, the skilled artisan can readily identify conserved domains between the two polypeptides. These conserved domains are preferred embodiments of the present invention.
FIG. 3
shows an analysis of the BMSP amino acid sequence. Alpha, beta, turn and coil regions; hydrophilicity and hydrophobicity; amphipathic regions; flexible regions; antigenic index and surface probability are shown, and all were generated using the default settings. In the “Antigenic Index or Jameson-Wolf” graph, the positive peaks indicate locations of the highly antigenic regions of the BMSP protein, i.e., regions from which epitope-bearing peptides of the invention can be obtained. The domains defined by these graphs are contemplated by the present invention.
The data presented in
FIG. 3
is also represented in tabular form in Table I. The columns in Table I are labeled with the headings “Res”, “Position”, and Roman Numerals I-XIV. The column headings refer to the following features of the amino acid sequence presented in FIG.
3
and Table I: “Res”: amino acid residue of SEQ ID NO:2 and
FIG. 1
; “Position”: position of the corresponding residue within SEQ ID NO:2 and
FIG. 1
; I: Alpha, Regions—Garnier-Robson; II: Alpha, Regions—Chou-Fasman; III: Beta, Regions—Garnier-Robson; IV: Beta, Regions—Chou-Fasman; V: Turn, Regions—Garnier-Robson; VI: Turn, Regions—Chou-Fasman; VII: Coil, Regions—Garner-Robson; VIII: Hydrophilicity Plot—Kyte-Doolittle; IX: Hydrophobicity Plot—Hopp-Woods; X: Alpha, Amphipathic Regions—Eisenberg; XI: Beta, Amphipathic Regions—Eisenberg; XII: Flexible Regions—Karplus-Schulz; XIII: Antigenic Index—Jameson-Wolf; and XIV: Surface Probability Plot—Emini.


REFERENCES:
patent: WO 98/20165 (1998-05-01), None
patent: WO 01/57188 (2001-02-01), None
patent: WO 01/57190 (2001-02-01), None
patent: WO 01/19860 (2001-03-01), None
Zhang et al., “Cloning and functional analysis o cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic Stem/Progenitor Cells,”Genome Research10:81546-1560 (2000).
GenBank Accession No. AF364517, Miele et al., “A novel erythroid-specific marker of transmissible spongiform encephalopathies,”Nat. Med.7(3):361-364 (2001).
Miele et al. “A novel erythroid-specific m

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