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 proliferation and metastasis, but little is known about how tumor-induced changes in the microenvironment affect benign cellular ecosystems. Applying dynamic in vivo imaging to a mouse model, we show that leukemic cell growth disrupts normal hematopoietic progenitor cell (HPC) bone marrow niches and creates abnormal microenvironments that sequester transplanted human CD34⁺ (HPC-enriched) cells. CD34⁺ cells in leukemic mice declined in number over time and failed to mobilize into the peripheral circulation in response to cytokine stimulation. Neutralization of stem cell factor (SCF) secreted by leukemic cells inhibited CD34⁺ cell migration into malignant niches, normalized CD34⁺ cell numbers, and restored CD34⁺ cell mobilization in leukemic mice. These data suggest that the tumor microenvironment causes HPC dysfunction by usurping normal HPC niches and that therapeutic inhibition of HPC interaction with tumor niches may help maintain normal progenitor cell function in 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

---

RNA Trafficking by Acute Myelogenous Leukemia Exosomes.

J. Huan, N. I. Hornick, M. J. Shurtleff, A. M. Skinner, N. A. Goloviznina, C. T. Roberts Jr, and P. Kurre (2013)
Cancer Res. 73, 918-929
 |  Abstract »  |  Full Text »  |  PDF »

Implantable microenvironments to attract hematopoietic stem/cancer cells.

J. Lee, M. Li, J. Milwid, J. Dunham, C. Vinegoni, R. Gorbatov, Y. Iwamoto, F. Wang, K. Shen, K. Hatfield, et al. (2012)
PNAS 109, 19638-19643
 |  Abstract »  |  Full Text »  |  PDF »

MM-associated anemia: more than "crowding out" HSPCs.

K. Podar (2012)
Blood 120, 2539-2540
 |  Full Text »  |  PDF »

Multiple myeloma-related deregulation of bone marrow-derived CD34+ hematopoietic stem and progenitor cells.

I. Bruns, R.-P. Cadeddu, I. Brueckmann, J. Frobel, S. Geyh, S. Bust, J. C. Fischer, F. Roels, C. M. Wilk, F. A. Schildberg, et al. (2012)
Blood 120, 2620-2630
 |  Abstract »  |  Full Text »  |  PDF »

Targeting acute myeloid leukemia cells with cytokines.

E. Ferretti, C. Cocco, I. Airoldi, and V. Pistoia (2012)
J. Leukoc. Biol. 92, 567-575
 |  Abstract »  |  Full Text »  |  PDF »

The evolving concept of cancer and metastasis stem cells.

I. Baccelli and A. Trumpp (2012)
J. Cell Biol. 198, 281-293
 |  Abstract »  |  Full Text »  |  PDF »

Human extramedullary bone marrow in mice: a novel in vivo model of genetically controlled hematopoietic microenvironment.

Y. Chen, R. Jacamo, Y.-x. Shi, R.-y. Wang, V. L. Battula, S. Konoplev, D. Strunk, N. A. Hofmann, A. Reinisch, M. Konopleva, et al. (2012)
Blood 119, 4971-4980
 |  Abstract »  |  Full Text »  |  PDF »

Bone marrow homing and engraftment of human hematopoietic stem and progenitor cells is mediated by a polarized membrane domain.

A. Larochelle, J. M. Gillette, R. Desmond, B. Ichwan, A. Cantilena, A. Cerf, A. J. Barrett, A. S. Wayne, J. Lippincott-Schwartz, and C. E. Dunbar (2012)
Blood 119, 1848-1855
 |  Abstract »  |  Full Text »  |  PDF »

Molecular Pathways: BCR-ABL.

D. Cilloni and G. Saglio (2012)
Clin. Cancer Res. 18, 930-937
 |  Abstract »  |  Full Text »  |  PDF »

Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia.

B. J. Frisch, J. M. Ashton, L. Xing, M. W. Becker, C. T. Jordan, and L. M. Calvi (2012)
Blood 119, 540-550
 |  Abstract »  |  Full Text »  |  PDF »

Mobilization of hematopoietic stem and leukemia cells.

M. A. Schroeder and J. F. DiPersio (2012)
J. Leukoc. Biol. 91, 47-57
 |  Abstract »  |  Full Text »  |  PDF »

MLL-ENL leukemia burden initiated in femoral diaphysis and preceded by mature B-cell depletion.

A. Jaracz-Ros, D. Lewandowski, V. Barroca, C. Lavau, and P.-H. Romeo (2011)
Haematologica 96, 1770-1778
 |  Abstract »  |  Full Text »  |  PDF »

The haematopoietic stem cell niche at a glance.

C. Lo Celso and D. T. Scadden (2011)
J. Cell Sci. 124, 3529-3535
 |  Full Text »  |  PDF »

How I treat patients who mobilize hematopoietic stem cells poorly.

L. B. To, J.-P. Levesque, and K. E. Herbert (2011)
Blood 118, 4530-4540
 |  Abstract »  |  Full Text »  |  PDF »

Galectin-3 (Gal-3) induced by leukemia microenvironment promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemia.

M. Yamamoto-Sugitani, J. Kuroda, E. Ashihara, H. Nagoshi, T. Kobayashi, Y. Matsumoto, N. Sasaki, Y. Shimura, M. Kiyota, R. Nakayama, et al. (2011)
PNAS 108, 17468-17473
 |  Abstract »  |  Full Text »  |  PDF »

Differential niche and Wnt requirements during acute myeloid leukemia progression.

S. W. Lane, Y. J. Wang, C. Lo Celso, C. Ragu, L. Bullinger, S. M. Sykes, F. Ferraro, S. Shterental, C. P. Lin, D. G. Gilliland, et al. (2011)
Blood 118, 2849-2856
 |  Abstract »  |  Full Text »  |  PDF »

The relationship between bone, hemopoietic stem cells, and vasculature.

S. L. Ellis, J. Grassinger, A. Jones, J. Borg, T. Camenisch, D. Haylock, I. Bertoncello, and S. K. Nilsson (2011)
Blood 118, 1516-1524
 |  Abstract »  |  Full Text »  |  PDF »

Drosophila: a model for studying genetic and molecular aspects of haematopoiesis and associated leukaemias.

M. Crozatier and A. Vincent (2011)
Dis. Model. Mech. 4, 439-445
 |  Abstract »  |  Full Text »  |  PDF »

Stromal Niche Cells Protect Early Leukemic FLT3-ITD+ Progenitor Cells against First-Generation FLT3 Tyrosine Kinase Inhibitors.

A. Parmar, S. Marz, S. Rushton, C. Holzwarth, K. Lind, S. Kayser, K. Dohner, C. Peschel, R. A. J. Oostendorp, and K. S. Gotze (2011)
Cancer Res. 71, 4696-4706
 |  Abstract »  |  Full Text »  |  PDF »

Niche contributions to oncogenesis: emerging concepts and implications for the hematopoietic system.

M. H. G. P. Raaijmakers (2011)
Haematologica 96, 1041-1048
 |  Abstract »  |  Full Text »  |  PDF »

Bone and the hematopoietic niche: a tale of two stem cells.

P. Bianco (2011)
Blood 117, 5281-5288
 |  Abstract »  |  Full Text »  |  PDF »

Making Cancer Stem Cells Homeless: The Rationale and Challenges behind Targeting the Cancer Stem Cell Niche.

Z. Li and J. Rich (2011)
Am. Assoc. Cancer Res. Educ. Book 2011, 151-154
 |  Full Text »  |  PDF »

Establishment of a xenograft model of human myelodysplastic syndromes.

Y. Muguruma, H. Matsushita, T. Yahata, S. Yumino, Y. Tanaka, H. Miyachi, Y. Ogawa, H. Kawada, M. Ito, and K. Ando (2011)
Haematologica 96, 543-551
 |  Abstract »  |  Full Text »  |  PDF »

Leukemia Stem Cells and Microenvironment: Biology and Therapeutic Targeting.

M. Y. Konopleva and C. T. Jordan (2011)
J. Clin. Oncol. 29, 591-599
 |  Abstract »  |  Full Text »  |  PDF »

Cholesterol Regulates VEGFR-1 (FLT-1) Expression and Signaling in Acute Leukemia Cells.

C. Casalou, A. Costa, T. Carvalho, A. L. Gomes, Z. Zhu, Y. Wu, and S. Dias (2011)
Mol. Cancer Res. 9, 215-224
 |  Abstract »  |  Full Text »  |  PDF »

The helix-loop-helix transcription factor TWIST is dysregulated in myelodysplastic syndromes.

X. Li, A. M. Marcondes, T. A. Gooley, and H. J. Deeg (2010)
Blood 116, 2304-2314
 |  Abstract »  |  Full Text »  |  PDF »

Angiopoietin-2 in CLL.

J. A. Burger (2010)
Blood 116, 508-509
 |  Full Text »  |  PDF »

Stem cells in cancer: instigators and propagators?.

M. R. Alison, S. Islam, and N. A. Wright (2010)
J. Cell Sci. 123, 2357-2368
 |  Abstract »  |  Full Text »  |  PDF »

Visualizing extravasation dynamics of metastatic tumor cells.

K. Stoletov, H. Kato, E. Zardouzian, J. Kelber, J. Yang, S. Shattil, and R. Klemke (2010)
J. Cell Sci. 123, 2332-2341
 |  Abstract »  |  Full Text »  |  PDF »

"Microenvironmental contaminations" induced by fluorescent lipophilic dyes used for noninvasive in vitro and in vivo cell tracking.

F. Lassailly, E. Griessinger, and D. Bonnet (2010)
Blood 115, 5347-5354
 |  Abstract »  |  Full Text »  |  PDF »

In vivo cellular imaging pinpoints the role of reactive oxygen species in the early steps of adult hematopoietic reconstitution.

D. Lewandowski, V. Barroca, F. Duconge, J. Bayer, J. T. Van Nhieu, C. Pestourie, P. Fouchet, B. Tavitian, and P.-H. Romeo (2010)
Blood 115, 443-452
 |  Abstract »  |  Full Text »  |  PDF »

Kinetics of normal hematopoietic stem and progenitor cells in a Notch1-induced leukemia model.

X. Hu, H. Shen, C. Tian, H. Yu, G. Zheng, R. XuFeng, Z. Ju, J. Xu, J. Wang, and T. Cheng (2009)
Blood 114, 3783-3792
 |  Abstract »  |  Full Text »  |  PDF »

The microenvironment in mature B-cell malignancies: a target for new treatment strategies.

J. A. Burger, P. Ghia, A. Rosenwald, and F. Caligaris-Cappio (2009)
Blood 114, 3367-3375
 |  Abstract »  |  Full Text »  |  PDF »

Inhibition of the SDF-1{alpha}-CXCR4 axis by the CXCR4 antagonist AMD3100 suppresses the migration of cultured cells from ATL patients and murine lymphoblastoid cells from HTLV-I Tax transgenic mice.

A. Kawaguchi, Y. Orba, T. Kimura, H. Iha, M. Ogata, T. Tsuji, A. Ainai, T. Sata, T. Okamoto, W. W. Hall, et al. (2009)
Blood 114, 2961-2968
 |  Abstract »  |  Full Text »  |  PDF »

The leukemic stem cell niche: current concepts and therapeutic opportunities.

S. W. Lane, D. T. Scadden, and D. G. Gilliland (2009)
Blood 114, 1150-1157
 |  Abstract »  |  Full Text »  |  PDF »

Altered cellular dynamics and endosteal location of aged early hematopoietic progenitor cells revealed by time-lapse intravital imaging in long bones.

A. Kohler, V. Schmithorst, M.-D. Filippi, M. A. Ryan, D. Daria, M. Gunzer, and H. Geiger (2009)
Blood 114, 290-298
 |  Abstract »  |  Full Text »  |  PDF »

This extraordinary extramedullary haematopoiesis.

M. S. Goligorsky (2009)
Nephrol. Dial. Transplant. 24, 2016-2017
 |  Full Text »  |  PDF »

Another nail in the AML coffin.

C. N. Abboud (2009)
Blood 113, 6045-6046
 |  Full Text »  |  PDF »

Optimal Mobilization of Normal and Leukemic Stem Cells via Modulation of Chemokine and Integrin Axes.

M. A. Schroeder, M. P. Rettig, P. Ramirez, and J. F. DiPersio (2009)
Am. Assoc. Cancer Res. Educ. Book 2009, 15-22
 |  Full Text »  |  PDF »

Darwin and evolutionary tales in leukemia.

M. Greaves (2009)
Hematology 2009, 3-12
 |  Abstract »  |  Full Text »  |  PDF »