Leukemia & Lymphoma, June 2011; 52(S2): 94–98
The microenvironment in hairy cell leukemia: pathways and potential therapeutic targets
JAN A. BURGER, MARIELA SIVINA, & FARHAD RAVANDI Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Abstract Hairy cell leukemia (HCL) cells accumulate and proliferate in the spleen and the bone marrow. In these tissue compartments, HCL cells interact with accessory cells, matrix proteins, and various cyctokines, collectively referred to as the ‘microenvironment.’ Surface receptors expressed on HCL cells and respective stromal ligands are critical for this cross-talk between HCL cells and the microenvironment. Chemokine receptors, adhesion molecules (integrins, CD44), the B cell antigen receptor (BCR), and CD40, expressed on the HCL cells, are likely to be critical for homing, retention, survival, and expansion of the neoplastic B cells. Some of these pathways are now targeted in first clinical trials in other mature B-cell malignancies. We summarize key aspects of the cellular and molecular interactions between HCL cells and their microenvironment. Also, we outline future prospects for therapeutic targeting of the microenvironment in HCL, focusing on CXCR4 and kinase inhibitors (Syk, Btk, phosphatidylinositol 3-kinase [PI3K]) that target B cell receptor signaling.
Keywords: Hairy cell leukemia (HCL), microenvironment, CXCR4, B cell receptor (BCR)
Intoduction Hairy cell leukemia (HCL) is a chronic B-cell malignancy of mature neoplastic B cells with hairy protrusions, characterized by splenomegaly and bone marrow infiltration and marrow fibrosis, causing cytopenias [1]. Over the past few years, there has been a paradigm shift in B cell malignancies and other cancers from primarily studying the malignant cells and their abnormal cytogenetics and signaling networks, toward also emphasizing the importance of the microenvironment in tumor progression [2,3]. This is based on compelling evidence suggesting that cross-talk with accessory stromal cells in specialized tissue microenvironments, such as the bone marrow and secondary lymphoid organs, favors disease progression by promoting malignant B cell growth and drug resistance [4,5]. Therefore, disrupting the communication of malignant B cells with theirmilieu is an attractive novel strategy for treating B-cell malignancies. This approach has been systematically studied in diseases that share some biological features with HCL, such as chronic lymphocytic leukemia (CLL) [2], and there is strong evidence that some of these pathways also could become attractive ther- apeutic targets in HCL.
Chemokine receptors and adhesion molecules in hairy cell leukemia
Chemokines and their receptors organize the recruit- ment and positioning of cells at each stage of the immune response, a system critically dependent upon coordination to get the right cells to the right place at the right time [6]. Chemokine receptors expressed on HCL cells are thought to function in a similar fashion, regulating the trafficking of hairy cells (HCs) between blood, lymphoid organs, and the bone marrow, and within sub-compartments within these tissues, in concert with adhesion molecules and other guidance cues. HCs express high levels of CXCR4 chemokine receptors (CD184) [7–9], while other B cell chemokine receptors that are critical for entry and positioning in lymph nodes (CXCR5, CCR7) are not expressed in HCL [9] (Figure 1), explaining the low propensity of HCL for lymph node involvement. HCs also express various adhesion molecules that cooperate with the chemokine receptors in tissue homing and retention [10–12], such as integrins and CD44. Among the different integrins, a4b1 (CD49d) and a5b1 (CD49e) are critical for HCL cell adhesion to vascular cell adhesion molecule-1 (VCAM-1;
Correspondence: Jan A. Burger, MD, PhD, Department of Leukemia, Unit 428, The University of Texas M. D. Anderson Cancer Center, PO Box 301402, Houston, TX 77230-1402, USA. Tel: (713)563-1487 or (713)792-1865. Fax: (713)794-4297. E-mail:
jaburger@mdanderson.org
ISSN 1042-8194 print/ISSN 1029-2403 online 2011 Informa UK, Ltd. DOI: 10.3109/10428194.2011.568649
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116 |
Page 117 |
Page 118 |
Page 119 |
Page 120 |
Page 121 |
Page 122