CD34+ or CD34−: which is the more primitive?

Abstract

Remarkable progress has been achieved in the characterization and isolation of primitive hematopoietic stem cells (HSC). HSC represent a very small subset of hematopoietic cells and provide self-renewal, possess differentiation capacity and allow a constant supply of the entire hematopoietic cell spectrum. Until recently, CD34 has been used as a convenient marker for HSC, since CD34 ؉ cells have been shown to possess colony-forming potential in short-term assays, maintain long-term colony-forming potential in in vitro cultures and allow the expression and differentiation of blood cells from different hematopoietic lineages in in vivo models. Clinical and experimental protocols have targeted CD34 ؉ cells enriched by a variety of selection models and have readily used these for transplantation, purging and gene therapies and targets for future organ replacement. Recent studies in murine and human models, however, have indicated that CD34 ؊ HSC exist as well, which possess engraftment potential and distinct HSC characteristics. These studies challenge the dogma that HSC are uniformly found in the CD34 ؉ subset, and question whether primitive HSC are CD34 ؉ or CD34 ؊ . In this review, results on murine and human CD34 ؉ and CD34 ؊ HSC, differences between them and their possible interactions are examined.

Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance

“…Recent studies have shown that CD34 Ϫ HSCs exist as well. 36,37 These CD34 Ϫ cells also possess HSC-specific characteristics, including the ability for hematopoietic engraftment. 36,37 This brings up the question as to whether the NPM1 mutant AML cells in fact represent a more primitive population of HSCs with a HOX gene signature.…”

Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice

“…CD34 has been long believed to be an HSC marker, but recent data revealed that the expression of CD34 is reversible and regulated by HSC activation. 22,23 Although the functional significance of CD34 remains unclear, L-selectin on leukocytes and E-selectin on vascular endothelium are putative ligands of CD34. [36][37][38] Our preliminary data showed both the CD34 þ and CD34 À fractions of SUG cells could similarly reconstitute leukemia in NOG mice.…”

“…[18][19][20] Intravenous injection of human leukemia cells into non-obese diabetes/severe combined immunodeficiency (NOD/SCID) mice, which is now the most common and most nearly physiological method to identify human HSCs in vivo, shows that leukemia cells expressing primitive cell surface makers such as CD34 þ and CD38 À can repopulate NOD/SCID mice regardless of the acute myeloid leukemia (AML) type. [21][22][23] The concept of leukemia stem cells (LSCs) may change current notions about how leukemia develops and how leukemia should be treated. However, the microenvironment for LSC is not yet well understood.…”

Characterization of a Lineage‐Negative Stem‐Progenitor Cell Population Optimized for Ex Vivo Expansion and Enriched for LTC‐IC

“…Modifications in previously described isolation protocols may also account for the variability of engraftment in immunocompromised animal models [17]. Due to the need to find an optimized population, we have developed a reproducible strategy for primitive cell harvest.…”