Pediatr Blood Cancer 2010;55:218–219

HIGHLIGHTby Sarah R. Vaiselbuh, MD*

How Do Leukemic Stem Cells Find Their Niche?Commentary on Faaij et al., page 344

Stem cells appear to be a functionally heterogeneous populationthat lives in cellular neighborhoods, called the stem cell niche.

The hematopoietic stem cell niche is defined as the habitat of stemcells within the bone marrow ecosystem, securing their longevityand “stemness.” The stem cell niche provides a micro-cosmos thatis both permissive and instructive for stem cell signaling and assuch offers a unique target for the development of novel stem celltherapeutics.

Acute myeloid leukemia (AML) is organized in a hierarchicalstructure that originates from a leukemic stem cell. Leukemic stemcells are in part defined by their ability to repopulate immune-deficient mice, resulting in a pattern of dissemination similar tothat seen in the original patients [1]. Similar to their healthy coun-terparts, leukemic stem cells appear to reside in bone marrowniches that are functionally defined by an endosteal and perivas-cular compartment. The black box of extramedullary niches forleukemic stem cell homing remains grossly unexplored. A list ofmolecular pathways are implicated in leukemic stem cell–nicheinteractions, the most elaborated being the CXCR4–CXCL12 axis[2]. The CXCR4 marrow homing receptor has been further devel-oped and is currently in clinical trial as a therapeutic target [3]. Highexpression of CXCR4 predicts extramedullary organ infiltration inchildhood acute lymphoblastic leukemia [4] and circulating AMLcells are enriched for CXCR4 [5]. Similarly, spleens harvested frommurine AML models are enriched for leukemia-initiation activity,suggesting that leukemia stem cells might find ways to manip-ulate normal niche signaling and other cell types to create new(extramedullary) microenvironments for homing [2]. Finally, ele-vated levels of CXCR microparticles have been detected in the bloodand bone marrow of AML patients, providing further evidence forchemokine/chemokine receptor axis intervening in AML traffickingand tissue dissemination [6].

In this issue of Pediatric Blood & Cancer, Faaij et al.address the role of chemokine/chemokine receptor interactions inextramedullary leukemia of the skin in childhood AML. Usingchemokine receptor analysis by flow cytometry and immunohis-tochemisty in blood, bone marrow, and affected skin samples, theyreport a significant CCR2 expression by AML cells in the periph-eral blood as well as in tumor cells of skin biopsy in patients withextramedullary disease (n = 15) compared to AML patients with-out extramedullary disease (n = 10). In addition, CCR5 and oneof its ligands CCL3 were expressed in all diseased skin biopsiesbut not in the peripheral blood or bone marrow samples. Theyconclude that CCR2 expression in circulating AML blast mayfacilitate homing to the skin. Monocyte chemoattractant protein-1(MCP-1) is a major chemoattractant for monocytes and mem-ory T cells by means of their binding to its specific cell-surfacereceptor, CC-chemokine receptor-2 (CCR2). CCR2 belongs to the

G-protein-coupled seven-transmembrane receptor superfamily. Theevidence in favor of CCR2 and MCP-1 having dominant roles inmonocyte chemotaxis and chronic inflammation was provided byCCR2 and MCP-1 knockout mice and studies in CC chemokinereceptor knockout have demonstrated that CCR2 and CCR5 arerequired not only for leukocyte recruitment but also for other aspectsof immune response development [7]. Abangan et al. describedthat hematopoietic stem cells are a novel source of carcinoma-associated circulating fibroblast precursors (CFPs). CFPs are ofmonocytic lineage and CFP recruitment and homing is facilitatedby MCP-1, regulating their contribution to the tumor microenvi-ronment [8]. If this is the case, measurement of the CCR2 ligandMCP-1 in AML can shed light on the mechanism how leukemicstem cells manipulate niche signaling to create new niches forhoming by attracting stromal cells to an extramedullary site. Inaddition, it would be worthwhile to evaluate the impact of thereceptor expression on disease-free survival and overall survival toidentify CCR2 as an independent prognostic factor for AML withchloromas.

Surprisingly, the authors suggest an unlikely role for CXCR4 andCXCR7 in skin homing because they found relatively low expres-sion of these receptors in peripheral blood and bone marrow AMLblasts. Caveat to this finding might be the fact that CXCR4 expres-sion in AML blast in peripheral blood is differentiation-related (lowexpression in M0, M1/2, and M6 AML but high in M3, M4/5) [9].Half of the patients (7/15) analyzed with extramedullary diseasewere staged as low differentiated AML (M0–M1/2) at diagnosis andno correlation was made of CXCR4 levels in skin lesions and blastdifferentiation stage. Dommange et al. [10] described that the abilityof AML blasts to exit from the bone marrow microenvironment, cir-culate, and anchor in extramedullar locations might be dependenton the CXCL12 phenotype. In a prospective study of 86 patientswith newly diagnosed AML, they found that the CXCL12 single-nucleotide polymorphism (SNP) G801A carrier status was highlyassociated with extramedullar locations in AML and that CXCR4expression on the surface of bone marrow blasts was correlatedwith leukemic dissemination in CXCL12 801A carriers. Althoughthey concluded that SNP 801A allele encoding CXCL12 is an inde-pendent risk factor for distant tissue infiltration by AML blasts,concomitant with a higher circulating blast count in the peripheral

Pediatric Hemato-Oncology & Stem Cell Transplantation, CohenChildren’s Medical Center, New Hyde Park, New York

*Correspondence to: Sarah R. Vaiselbuh, Pediatric Hemato-Oncology& Stem Cell Transplantation, Cohen Children’s Medical Center, 269-0176th Ave., New Hyde Park, NY 11040. E-mail: smeeus@nshs.edu

Received 8 March 2010; Accepted 8 March 2010

© 2010 Wiley-Liss, Inc.DOI 10.1002/pbc.22554Published online in Wiley InterScience(www.interscience.wiley.com)

Highlight 219

blood but not in the bone marrow, these findings were refuted byPonziani et al. [11]. They determined CXCL12 801A carrier statusin a retrospective analysis of 214 adult patients with AML. They didnot find a meaningful difference in percentage of blasts neither inperipheral blood nor bone marrow based on CXCL12 G801 A poly-morphism. In addition, they concluded that there is no significantimpact of the CXCL12 genotype on disease outcome. Measurementof SDF-1 production in patients’ serum in vivo or by the bone mar-row stroma of CXCL12 G801A carriers in vitro might shed lighton the functional relevance of the polymorphism carrier status andcan provide an explanation for the discrepancy in the describeddata.

The analysis of the role of chemokine axis CXCL12/CXCR4 indissemination and onset of extramedullary AML is just one exampleof the complexity involved in the migration and homing processesof AML blasts. The findings described in this study add new piecesto the puzzling question how leukemic stem cells find their way tothe niches. The mechanisms of cell trafficking associated with thechemokine system can be investigated in pediatric AML by func-tional analysis of the newly described chemoreceptor expression inchemotaxis assays.

As more data emerge on the genetic signature of AML blastsin their stem cell niches and chemoreceptor profiling, we will beable to develop fine-tuned targeted therapies to disrupt the niche,medullary as well as extramedullary, and we can hope for moreeffective treatment in childhood AML.

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Pediatr Blood Cancer DOI 10.1002/pbc