Bone marrow specific protein

#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.

#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 a nucleate 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.

#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 E-42 (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.

#Definitions

#The following definitions are provided to facilitate understanding of certain terms used throughout this specification.

#In the present invention, “isolated” refers to material removed from its original environment (e.g., the natural environment if it is naturally occurring), and thus is altered “by the hand of man” from its natural state. For example, an isolated polynucleotide could be part of a vector or a composition of matter, or could be contained within a cell, and still be “isolated” because that vector, composition of matter, or particular cell is not the original environment of the polynucleotide. In another embodiment, an “isolated” nucleic acid molecule does not encompass a chromosome isolated or removed from a cell or a cell lysate (e.g., a “chromosome spread”, as in a karyotype). In yet another embodiment, an “isolated” nucleic acid molecule does not encompass a cDNA or genomic library which contains a sequence which encodes BMSP. In further embodiments, an “isolated” nucleic acid molecule does not encompass any collection of vectors which contain exceptionally large DNA, RNA, or cDNA inserts with respect to the BMSP sequence disclosed herein (for example, cDNA or genomic libraries, or YAC or BAC artificial chromosomes, and the like) which contain a sequence encoding BMSP.