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Objective-Little is known about the relations of telomere lengths among leukocyte subsets and between leukocytes and cells up the hematopoietic hierarchy. This information is relevant, since telomere dynamics in granulocytes were postulated to mirror those of hematopoietic stem cells (HSCs).Subjects and Methods-We examined in newborns' cord blood (UCB) the relationships of telomere length in hematopoietic progenitor cells (HPCs) (CD34 + CD45 − ) with that in T lymphocytes and in granulocytes. In addition, we correlated telomere length in granulocytes with that in whole leukocyte samples of individuals with age range between birth and 100 years.Results-In the UCB, we found strong correlations of telomere length in HPCs with telomere lengths in T lymphocytes (r ranging from 0.882-0.935, p ranging from 0.0038-0.0007) and in granulocytes (r=0.930, p=0.0072). At birth, strong correlations were also observed between telomere length in granulocytes and that in all leukocytes (r=0.979, p=0.0003). Throughout the human lifespan, the relationship between telomere length in granulocytes and that in all leukocytes was r>0.980, p<0.0001.Conclusions-Robust synchrony exists among leukocyte subsets throughout the human lifespan; individuals with relatively long (or short) telomeres in one leukocyte subset have long (or short) telomeres in other leukocyte subsets. Moreover, telomere length in leukocytes reflects its length in cells up the hematopoietic hierarchy, i.e., HPCs and, by inference, HSCs. Strong links have been found by many studies between leukocyte telomere length and a host of aging-related diseases. Our findings suggest, therefore, that that these links might be traced to telomere dynamics in HSCs.

IntroductionMyeloma bone disease is characterized by lytic bone lesions with little or no reactive new bone formation. Up to 80% of multiple myeloma (MM) patients present with bone pain, and over 70% of the patients will develop pathologic fractures during the course of their disease (1). Bone destruction in myeloma is a local event in which lesions only occur adjacent to myeloma cells. These data suggest that MM cells produce factors or induce factors that stimulate osteoclast (OCL) formation. We have used an expression cloning approach with a cDNA library constructed from RNA obtained from freshly isolated bone marrow samples from MM patients and screened it for osteoclast-activating factors (OAFs) that induce OCL formation in human and murine marrow cultures. We identified macrophage inflammatory protein 1-α (MIP-1α) as an OAF produced by myeloma cells in vivo (2). MIP-1α induced formation of bone-resorbing OCLs in human marrow cultures, acted directly on OCL precursors, and did not upregulate RANK ligand (RANKL) expression (3). Furthermore, MIP-1α enhanced the effects of IL-6 and RANKL, cytokines present in myeloma marrow, on OCL formation (3). Previously, Kukita and coworkers (4) reported that MIP-1α induces OCL formation in rat bone marrow cultures, and Fuller and coworkers (5) have shown that MIP-1α is chemotactic for OCLs. More importantly, MIP-1α levels are increased in marrow plasma from myeloma patients with active disease, whereas MIP-1α levels are reduced to almost normal levels in patients who are in complete remission, or have inactive disease, or who have stage I myeloma (2). Furthermore, addition of a neutralizing Ab to MIP-1α blocked the OAF activity present in bone marrow plasma samples from patients with myeloma (2). The purpose of the current study was to determine the role of MIP-1α in an in vivo model of human myeloma bone disease. We reported previously that intravenous injection of the human myeloma-derived cell line, ARH, into sublethally irradiated SCID mice induces myeloma in these animals (1). These mice develop all the characteristics of myeloma bone disease, including lytic bone lesions, hypercalcemia, and increased OCL formation in areas adjacent to the myeloma cells. ARH cells produce high levels of MIP-1α. Therefore, ARH cells were stably transfected with either an antisense construct to MIP-1α or an empty vector and transplanted into SCID mice to determine the role of MIP-1α in this animal model of human myeloma bone disease. We recently identified macrophage inflammatory protein 1-α (MIP-1α) as a factor produced by multiple myeloma (MM) cells that may be responsible for the bone destruction in MM (1). To investigate the role of MIP-1α in MM bone disease in vivo, the human MM-derived cell line ARH was stably transfected with an antisense construct to MIP-1α (AS-ARH) and tested for its capacity to induce MM bone disease in SCID mice. Human MIP-1α levels in marrow plasma from AS-ARH mice were markedly decreased compared with controls treated with ARH cells transfected with empty ...

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Adhesion molecules and stromal cell-derived factor-1 (SDF-1)/ CXCR4 signaling play key role in homing and mobilization of hematopoietic progenitor (HPC) and hematopoietic cancer clonogenic cells (HCC). High expression of VLA-4 is required for homing of HPC and HCC, whereas downregulation of these molecules is required for successful mobilization of HPC and HCC. Upregulation and activation of the SDF-1/CXCR4 signaling is required for homing of HPC and HCC, whereas disruption of the SDF-1 signaling is required for mobilization of HPC and HCC. Hence, mobilizations of HPC and HCC occur concurrently. It is proposed that drug resistance evolves as a result of repeated cycles of chemotherapy. Following each cycle of chemotherapy, HCC lose adhesion molecules and SDF-1 signaling. Surviving cells, released from tumor sites, circulate until re-expression of adhesion molecules and CXCR4 occurs, then homing to stroma of distal tissues occurs. Cytokines secreted by cells in the new microenvironment induce proliferation and drug resistance of HCC. This process is amplified in each cycle of chemotherapy resulting in disease progression. A novel model for treatment is proposed in which circulating HCC are the target for clinical intervention, and concurrent treatment with chemotherapy and antilineage-specific antibodies will result in abrogation of the 'vicious cycle' of conventional anticancer therapy.