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Biology Articles » Cell biology » Concise Review: Telomere Biology in Normal and Leukemic Hematopoietic Stem Cells » Introduction

Introduction
- Concise Review: Telomere Biology in Normal and Leukemic Hematopoietic Stem Cells


The notion that cancer may be underpinned by the malignant transformationof a critical stem cell population, although relatively recentin terms of solid tumor biology, is one that has been acceptedfor many years by scientists studying leukemia. The abilityto isolate and characterize the leukemic stem cell (LSC) populationhas facilitated steady progress in understanding how such cellsmay attain an immortal phenotype. One prerequisite is the abilityto maintain telomere length via expression of the widely conservedenzyme telomerase. This review will summarize the current understandingof telomere biology as it relates to hematopoietic stem cells,from steady state normality through to stem cell transplantationand manipulation and finally in hematological malignancy.

The bone marrow of an adult human being is estimated to producein excess of 1011 blood cells per day, all of which are ultimatelyderived from pluripotent hematopoietic stem cells (HSC) (reviewedin [1]). These unique cells, with their paradoxical leukemogenicand therapeutic potential (for example, in HSC transplantation),have stimulated enormous research effort. All mature circulatingblood cells are derived from a relatively small number of HSCvia a successive series of intermediate progenitors displayingsteadily increasing lineage commitment (reviewed in [2]). Sucha hierarchical model of hemopoiesis has provided a paradigmfor the development of other tissues and, more recently, leukemogenesisand tumorigenesis [3]. Candidate HSC can be isolated and characterizedboth functionally (e.g., by the ability of single cells to reconstitutemultilineage hemopoiesis in a mouse model or by the abilityto establish long-term cell culture in vitro) and by immunophenotyping.The latter is commonly performed in the clinical and laboratorysetting using the CD34 antigen (a surface glycoprotein) as asurrogate HSC marker [4]. The properties of CD34+ cells arewell-characterized from both research and clinical perspectives,although it is apparent that even the CD34+ progenitor cellpopulation is in itself extremely heterogeneous [5]. True HSCmost likely represent a tiny proportion of CD34+ cells: CD34+cells negative (or low) for CD38, thy-1, and CD71 are enrichedfor HSC activity [6]. Such cells are predominantly quiescent(i.e., in G0) [7], and it has been estimated by mathematicalmodeling that they divide only once every 1–2 years [8].Unfortunately, such cells are difficult to study in vitro; inaddition to their rarity, the mechanism of self-renewal versusdifferentiation is not clear, and candidate HSC will expandand differentiate in culture conditions, with acquisition oflineage-specific markers and concomitant loss of stem cell phenotype.

Although HSC have an enormous capacity to self-renew and/ordifferentiate, this capacity appears to be finite; for example,murine HSC can only be serially transplanted 5–7 timesin mice before hemopoiesis is exhausted [9]. Although it ispossible that extrinsic stress (i.e., ex vivo handling of cells,engraftment in a hostile bone marrow microenvironment, etc.)may contribute to this observation, the concept that an intrinsicmechanism is operating to limit cell expansion, by registeringaccumulated cell divisions, has always been attractive. Therefore,the discovery that telomeres (DNA-protein "caps" that existat all eukaryotic chromosomal termini) shorten with each celldivision in vitro [10] and with age in vivo [1113] subsequentlyimplicated this as a likely mechanism.


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