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Leukemic Cells Create Bone Marrow Niches That Disrupt the Behavior of Normal Hematopoietic Progenitor Cells
Angela Colmone,
Maria Amorim,
Andrea L. Pontier,
Sheng Wang,
Elizabeth Jablonski,
Dorothy A. Sipkins*
Abstract:
The host tissue microenvironment influences malignant cell proliferationand metastasis, but little is known about how tumor-inducedchanges in the microenvironment affect benign cellular ecosystems.Applying dynamic in vivo imaging to a mouse model, we show thatleukemic cell growth disrupts normal hematopoietic progenitorcell (HPC) bone marrow niches and creates abnormal microenvironmentsthat sequester transplanted human CD34+ (HPC-enriched) cells.CD34+ cells in leukemic mice declined in number over time andfailed to mobilize into the peripheral circulation in responseto cytokine stimulation. Neutralization of stem cell factor(SCF) secreted by leukemic cells inhibited CD34+ cell migrationinto malignant niches, normalized CD34+ cell numbers, and restoredCD34+ cell mobilization in leukemic mice. These data suggestthat the tumor microenvironment causes HPC dysfunction by usurpingnormal HPC niches and that therapeutic inhibition of HPC interactionwith tumor niches may help maintain normal progenitor cell functionin the setting of malignancy.
Department of Medicine, Section of Hematology/Oncology, The University of Chicago, 5841 South Maryland Avenue MC 2115, Chicago, IL 60637, USA.
* To whom correspondence should be addressed: E-mail: dsipkins{at}medicine.bsd.uchicago.edu
Hematopoietic progenitor cells (HPCs) home to and engraft inhighly specific bone marrow (BM) microenvironments, or niches,that regulate their survival, proliferation, and differentiation(1, 2). These niches have been defined by the association ofparticular stromal cell types and by their elaboration or secretionof specific signaling molecules, growth factors, and cytokines(3). At least two distinct HPC-supportive niches have been identifiedin the BM: an osteoblastic niche in which molecules includingbone morphogenetic protein, osteopontin, angiopoietin-1, andNotch appear to play important regulatory roles; and a vascularniche that remains to be molecularly defined (4–8).
Although defects in hematopoiesis are frequently observed inpatients with malignant involvement of the BM, the molecularbases of these phenomena, and whether they might reflect perturbationsin HPC-supportive niches, are unknown. Suppression of normalhematopoiesis can occur in the setting of relatively low tumorburden and thus does not necessarily reflect anatomic "crowdingout" of benign cells.
Using a severe combined immunodeficiency (SCID) mouse xenograftmodel of Nalm-6 pre-B acute lymphoblastic leukemia (ALL), wehave shown that malignant cells metastasize to specific stromalcell–derived factor–1(SDF-1)–positive vascularniches in the BM that overlap with perivascular HPC niches (9).To investigate whether benign and malignant cells compete forniche resources, we used real-time, in vivo confocal and multiphotonmicroscopy imaging approaches that allowed us to colocalizefluorescently labeled BM antigens with fluorescently labeledhuman CD34+ cells, which are highly enriched in HPCs, and fluorescenttumor cells (10). For intravenous transplant into mice, we harvestedCD34+ cells from human cord blood and from the peripheral bloodof human donors who had been treated with cytokines to stimulatemobilization of HPCs from the BM. Both of these populationsare currently used for therapeutic BM transplantation in humans.Serial imaging of individual mice permitted us to observe cellularmigration and proliferation in the calvarial BM over multipletime points from initial BM homing of circulating CD34+ cellsthrough long-term CD34+ cell engraftment (12 weeks or more aftertransplantation) [Fig. 1A and figs. S1 and S2 (10)].
Fig. 1.. Leukemia-induced changes in the BM microenvironment disrupt CD34+ cell homing. (A) Diagram of mouse calvarial BM vasculature. In control mice, CD34+ cells predominantly home to parasagittal sinusoidal vasculature. A major fraction of CD34+ cells engraft in this parasagittal region after homing, whereas other CD34+ cells migrate to more lateral osteoblastic and vascular niches. (B) SDF-1 (red) is highly expressed in the parasagittal sinusoidal region (CD34+ cell homing sites) of control mice. Nalm-6–GFP cells (green) preferentially home to and proliferate in this area, leading to marked down-regulation of SDF-1 expression, here shown at 35 days after Nalm-6–GFP engraftment. Central vein (cv) is labeled for orientation. (C) CD34+ cells (white) home to the SDF-1–positive parasagittal vascular niches in control mice. CD34+ cells aberrantly home to SDF-1+–negative, lateral regions in tumor (green)–engrafted mice. Scale bars (B and C), 250 µm.
[View Larger Version of this Image (52K GIF file)]
SDF-1 is an important chemoattractant for HPC homing to theBM and plays a key role in maintaining hematopoiesis (11–13).Because SDF-1 expression is up-regulated in regions of hypoxiaor inflammation (14, 15), we hypothesized that SDF-1 proteinlevels would be increased in the tumor niche. Surprisingly,however, when we assessed the mice for BM SDF-1 expression 1month after initial Nalm-6–GFP (green fluorescent protein)engraftment, we found that SDF-1 was markedly down-regulatedin regions of heavy tumor growth (Fig. 1B and figs. S3 and S4).These areas of extensive tumor proliferation and SDF-1 down-regulationcorresponded to typical CD34+ cell homing niches.
Given that leukemic proliferation occurred preferentially withinCD34+ cell homing niches and disrupted chemokine SDF-1 expressionat these sites, we next examined whether CD34+ cell BM homingwas altered in leukemic mice. Nalm-6–GFP leukemic miceversus control mice were engrafted intravenously with purified,fluorescently labeled human CD34+ cells. Whereas in controlmice CD34+ cell homing localized to SDF-1–positive parasagittalvascular niches, in leukemic mice CD34+ cell homing was redirectedto atypical lateral microenvironments (Fig. 1C and fig. S5).This finding did not reflect an inability of cells to enterparasagittal regions in leukemic mice, because video-rate imagingconfirmed that the cells transited freely through parasagittaltumor-associated vasculature [movies S1 and S2 (10)]. Furthermore,when CD34+ cells were pretreated with pertussis toxin (an inhibitorof chemokine receptor Gi-mediated signaling) or with AMD3100(a small-molecule antagonist of the SDF-1 receptor CXCR4), therewas no significant decrease in CD34+ cell homing to the BM intumor mice (figs. S6 and S7). These data suggest that in leukemicmice, CD34+ cells homed to atypical regions through an SDF-1–and chemokine-independent mechanism.
Although CD34+ cells were able to traffic to BM in leukemicmice, our observation that initial homing occurred in abnormalvascular niches raised the possibility that subsequent engraftmentwould be altered. We therefore performed serial imaging studiesof individual mice to assess the intra-BM movement of CD34+cells. Surprisingly, most CD34+ cells did not remain at sitesof initial homing or migrate to other tumor-free niches. Instead,within days, the vast majority of the transplanted cells aberrantlymigrated to SDF-1–negative tumor beds, suggesting thatthe tumor had created a new malignant niche capable of recruitingCD34+ cells (Fig. 2A).
Fig. 2.. The malignant microenvironment, or niche, attracts CD34+ cells, but does not maintain CD34+ cell pool size or response to cytokine mobilization. (A) Few CD34+ cells colocalize with tumor upon homing to BM (day 0: 25.6 ± 6.7%), yet CD34+ cells migrate into tumor niches over time (day 7: 82.1 ± 4.5%, normalized to total CD34+ cells in BM; n = 4 mice, ***P < 0.0001). (B) Serial imaging of mice from 12 to 16 weeks after CD34+ cell (white) transplant reveals that long-term transplanted CD34+ cells abandon normal niches (representative area A3 pretumor) after leukemia (green) engraftment. Conversely, CD34+ cells in leukemic mice migrate to tumor regions (area A8 posttumor) where CD34+ cells do not normally localize. Most of the long-term transplanted CD34+ cells are found within tumor beds (65.9 ± 7%; n = 6 mice) in mice imaged 1 month after tumor engraftment. Tumor involves only 20 to 30% of BM at this time point. (C and D) Fewer CD34+ cells are harvested from BM of leukemic versus control mice at 7 days (C) [day 7: 55.2 ± 8.5%; n = 4 mice (leukemia), n = 2 mice (control), *P = 0.029] and 16 weeks (D) (16 weeks: 21.7 ± 3.3%; n = 4(leukemia), n = 4 (control), **P = 0.005) after CD34+ cell transplant. (E) CD34+ cells mobilize from BM upon G-CSF treatment of naïve (98.6 ± 0.2%), but not leukemic (13.8 ± 7%), mice (serial imaging of the same areas; n = 3 mice each, leukemia and control, ***P < 0.0005). Scale bars (A, B, and E), 250 µm.
[View Larger Version of this Image (50K GIF file)]
To determine if the malignant niche could also compete for CD34+cells previously established in normal BM niches, we introducedNalm-6–GFP into mice that had been transplanted with CD34+cells 12 to 16 weeks earlier. One month after tumor engraftment,most CD34+ cells abandoned tumor-free niches for malignant niches(Fig. 2B). To determine if the malignant niche was able to maintainthe new resident CD34+ populations, we harvested human CD34+cells from leukemic and control mice by magnetic bead selectionand quantified the cells by flow cytometry. Significantly fewerCD34+ cells (55.2 ± 8.5%) were recovered from leukemicmice 1 week after CD34+ cell transplantation when compared withcontrol mice (Fig. 2C). In long-term CD34+ cell–transplantedmice subsequently engrafted with leukemia, CD34+ cell countsalso declined significantly (21.7 ± 3.3%) over time inleukemic versus control mice (Fig. 2D). These data suggest thatthe malignant niche, although outcompeting native niches forCD34+ cell localization, fails to preserve the CD34+ cell poolsize seen in normal mice.
HPCs are routinely collected for autologous or allogeneic transplantby harvest from the peripheral blood after these cells are mobilizedout of the BM by treatment of patients with the cytokine granulocytecolony-stimulating factor (G-CSF). However, the presence ofresidual BM disease is associated with decreased CD34+ cellmobilization into the peripheral circulation after cytokinetreatment (16). Addition of the investigational agent AMD3100to enhance mobilization can also fail to yield adequate stemcell numbers (17). Although some of this effect may be relatedto stromal damage from chemo- and radiotherapy, a clear causefor mobilization failure has not been established (18). We thereforeexamined the effect of malignant niche migration in leukemicmice on CD34+ cell mobilization. CD34+ cells engrafted in leukemicmice minimally mobilized in response to a 5-day course of G-CSFcompared with controls (Fig. 2E). Mobilization was not enhancedby the addition of AMD3100 (fig. S8).
We next explored the molecular mechanism responsible for CD34+cell migration into the malignant niche, with the goal of correctingCD34+ cell dysfunction by inhibiting the transit of these cellsfrom normal microenvironments. To investigate the possibilitythat the malignant cells might be the source of chemoattractants,we performed transwell migration assays with CD34+ cells andconditioned media (CM) from Nalm-6–GFP, primary humanALL, and primary human acute myeloblastic leukemia (AML) cellcultures. Relative to control media, CD34+ cells migrated insignificantly greater numbers (by a factor of 3.5) to leukemiaCM (Fig. 3A). Addition of SDF-1 to CM had an additive, but notsynergistic, effect on migration (fig. S9). We next screenedCM by Western blot for molecules with chemotactic activity forCD34+ cells. Among our initial candidates was stem cell factor(SCF), an HPC growth factor and chemoattractant believed toplay a role in HSC localization to endosteal niches (19–22).SCF is produced by a wide variety of solid tumors (23–26).AML cell lines and primary AML cells have been shown to produceSCF RNA transcripts, but expression of SCF by hematologic malignanciesis not well defined (27). Figure 3B and fig. S10 show that SCFprotein is clearly present in leukemia-CM.
Fig. 3.. SCF mediates CD34+ cell migration into the malignant niche, as well as mobilization failure and decrease in CD34+ cell number in leukemic mice. (A) CD34+ cells migrate in vitro in response to leukemia-conditioned media (CM). (Control media: 16,137 ± 3799; SDF-1: 37,056 ± 3058; Nalm6-CM: 57,086 ± 14686; ALL-CM: 59,311 ± 17,495; AML-CM: 79,933 ± 933; n = 3 experiments; SDF-1:control, *P = 0.0014; SDF-1:all leukemia-CM, *P = 0.009; SDF-1:Nalm6-CM, *P = 0.026; SDF-1:ALL-CM, *P = 0.020; SDF-1:AML-CM, ***P < 0.0001). (B) SCF protein is secreted by Nalm-6–GFP in vitro. (C) In vivo imaging demonstrates increased SCF (red) expression in a tumor (green)–engrafted versus naïve mouse. Scale bars, 250 µm. (D) Immunohistochemistry shows hSCF (brown) expression in tumor-engrafted but not control mouse femur. Scale bars, 100 µm. (E and F) CD34+ cells (white); Nalm-6–GFP (green) (E) Neutralizing treatment with anti-SCF inhibits CD34+ cell migration into tumor 7 days after CD34+ cell transplant into leukemic mice (control: 76.1 ± 5.6%; anti-SCF: 36.7 ± 8.3%; n = 5 mice each, control and anti-SCF, *P = 0.008). Scale bars, 250 µm. (F) Neutralizing anti-SCF inhibits migration of long-term engrafted (LTE) CD34+ cells into the malignant niche. Treatment began 12 weeks after CD34+ cell transplant (at the time of tumor engraftment) and continued for 4 weeks (control: 79.6 ± 6.3%; anti-SCF: 59.3 ± 0.4%; n = 2 mice each, control and anti-SCF). Scale bars, 250 µm. (G) Neutralizing anti-SCF restores G-CSF–mediated CD34+ cell mobilization in leukemic mice (control: 13.75 ± 7.0%; anti-SCF: 68.0 ± 6.0%; n = 3 mice each, control and anti-SCF, **P = 0.004). (H) Seven days after transplant, increased numbers of CD34+ cells were isolated from BM of leukemic mice treated with neutralizing anti-SCF versus control IgG (anti-SCF: 211 ± 23, normalized to control = 100; n = 2 mice each, control and anti-SCF, *P = 0.04).
[View Larger Version of this Image (88K GIF file)]
To assess whether SCF expression was up-regulated in the leukemicniche in our mouse model, we performed in vivo immunoimagingof control versus Nalm-6–GFP leukemic mice using fluorescentlylabeled mouse/human cross-reactive antibodies to SCF (anti-SCF).Whereas only a faint SCF signal was detectable at baseline incontrol mouse calvarial BM, SCF was highly expressed in miceimaged 1 month after Nalm-6–GFP engraftment (Fig. 3C).Immunohistochemical staining of mouse femurs confirmed thathuman SCF (hSCF) was present at high abundance in this marrowcompartment (Fig. 3D). In addition, Western blotting of controlversus leukemic BM showed expression of human SCF protein product(fig. S11). Quantitative reverse transcription–polymerasechain reaction demonstrated a significant decrease in mouseSCF RNA transcript copy numbers, suggesting that leukemic cellsconstituted the major source of SCF in the malignant microenvironment(fig. S12).
To determine whether CD34+ cell migration into the malignantniche could be prevented by inhibition of SCF activity, we treatedNalm-6–GFP leukemic mice with SCF-neutralizing antibodiesbeginning 1 day before CD34+ cell engraftment. We found thatat 7 days after CD34+ cell engraftment, significantly fewerCD34+ cells had migrated into tumor niches in treated (37%)versus untreated (76%) mice (Fig. 3E). We also treated long-termCD34+ cell–engrafted mice (12 to 16 weeks) with SCF-neutralizingantibodies beginning 1 day before Nalm-6–GFP engraftmentand continuing for 30 days. Again, fewer CD34+ cells exitednormal niches for the malignant niche compared with the control(Fig. 3F). To determine if prevention of CD34+ cell egress frombenign niches also rescued CD34+ cell function in leukemic mice,we administered a 5-day course of G-CSF (to induce CD34+ cellmobilization) to mice that had been treated with SCF-neutralizingantibody, as well as to control immunoglobulin G (IgG)–treatedmice. Sixty-eight percent of CD34+ cells in neutralizing antibody–treatedmice mobilized in response to cytokine stimulation versus 14%in untreated mice (Fig. 3G). In another set of experiments,leukemic mice were treated with SCF-neutralizing antibody versuscontrol IgG beginning 1 day before transplant of CD34+ cells.Mice were killed after 7 days for CD34+ cell harvest and quantitation.More than twice as many CD34+ cells were obtained from treatedmice (Fig. 3H). These data suggest that CD34+ cell pool sizecould be maintained in leukemic mice by inhibiting CD34+ cellengagement with the malignant niche.
To extend our observations with the Nalm-6 ALL cell line toprimary human disease, we performed similar experiments withcells isolated from BM aspirates of ALL or AML patients. Imagingof mice 8 weeks after engraftment of primary pre-B ALL or AMLin nonobese diabetic–severe combined immunodeficiency(NOD-SCID) mice revealed pronounced up-regulation of SCF signalin the calvarial BM (Fig. 4A and fig. S13). CD34+ cells engraftedin these mice exhibited migration into SCF+ domains similarto that in Nalm-6–GFP leukemic mice (Fig. 4B). CD34+ cellsalso failed to respond to G-CSF mobilization (Fig. 4C).
Fig. 4.. Primary leukemic cells from patients with ALL and AML create abnormal CD34+ cell niches; human ALL BM biopsies demonstrate marked up-regulation of SCF. (A) SCF (red) expression is markedly up-regulated in ALL-engrafted versus control mice. CD34+ cells (white) localize to regions of high SCF expression. Scale bars, 250 µm. (B) CD34+ cells migrate into the malignant niche in ALL and AML-engrafted mice (ALL: 72.7%; AML: 73.6%). (C) CD34+ cells do not respond to G-CSF mobilization in ALL-engrafted mice (control: 80.4%, ALL: 7.8%). (D) Representative micrographs of SCF (brown) immunohistochemical staining in a diagnostic BM biopsy from a patient with pre-B ALL versus a normal BM biopsy. Scale bars, 100 µm. (E) Quantitative analysis of SCF immunostaining intensity in ALL versus normal BM biopsies (ALL: 814 ± 88, n = 7 patients; normal: 364 ± 107, n = 3 patients; *P = 0.004).
[View Larger Version of this Image (76K GIF file)]
Finally, we determined whether changes in SCF expression couldbe detected in initial diagnostic BM samples from patients withpre-B ALL. Normal BM biopsies (no evidence of disease) and BMbiopsies with known ALL involvement were assayed for SCF byimmunohistochemistry of paraffin-embedded sections. As seenin representative micrographs in Fig. 4D, basal expression waslow in all three normal controls, whereas SCF staining was markedlyelevated (by a factor of 2; Fig. 4E) in all seven patient samples.
We have shown that leukemic proliferation in the BM alters thestromal microenvironment and creates malignant niches that outcompetenative HPC niches for CD34+ cell engraftment. Normal CD34+ cellsengaged by the malignant niche exhibit abnormal behavior. Ourdata suggest that therapeutic targeting of SCF may increasethe hematopoietic reserve and improve outcomes in BM transplantationand autologous stem cell harvest in the setting of hematologicmalignancy. The findings from our xenograft model, however,require confirmation in human studies.
Our results raise many questions about the nature of tumor-hostinteractions: Do leukemic cells reorganize the molecular microenvironmentspecifically to entrap HPCs, or is the creation of competitiveHPC niches a coincidental side effect of leukemic growth? Conceivably,derangements in hematopoiesis and HPC mobilization could impairanti-tumor immune responses. Of note, SCF neutralization didnot significantly inhibit Nalm-6 proliferation in our model,and indeed Nalm-6 cells down-regulate their expression of theSCF receptor, KIT, in vivo (fig. S14). These findings, althoughnot definitive, suggest that Nalm-6 SCF production does notprincipally serve to fuel autocrine tumor growth. Future studiesthat elucidate the intricacies of these tumor-host interactionsare expected to further our understanding of stem and progenitorcell dysfunction in cancer and expose new therapeutic targets.
We thank A. Chenn, K. Cohen, L. Godley, and R. Salgia for critical discussions and reading of the manuscript; A. Chenn for assistance with retroviral cell transduction; A. Wickrema for help with CD34+ purification; V. Bindokas for imaging expertise; and S. Gurbuxani for assistance with histopathology interpretation. Supported by a grant from the Illinois Regenerative Medicine Institute (IRMI), an NIH (National Cancer Institute) K08 award (5K08CA112126-02), and an NIH Director's DP2 award (1DP2OD002160-01). A patent application related to this work has been filed by the University of Chicago.
Received for publication 7 August 2008. Accepted for publication 19 November 2008.
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1 month after initial Nalm-6–GFP (green fluorescent protein) engraftment, we found that SDF-1 was markedly down-regulated in regions of heavy tumor growth (
i-mediated signaling) or with AMD3100 (a small-molecule antagonist of the SDF-1 receptor CXCR4), there was no significant decrease in CD34+ cell homing to the BM in tumor mice (figs. S6 and S7). These data suggest that in leukemic mice, CD34+ cells homed to atypical regions through an SDF-1– and chemokine-independent mechanism. 
