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Abstract
Differentiation therapy of leukemia is the treatment of leukemia cells with biological or chemical agents that induce the terminal differentiation of the cancer cells. It is regarded as a novel and targeted approach to leukemia treatment, based on our better understanding of the hematopoietic process and the mechanisms of its deregulation during leukemogenesis. Clinically, differentiation therapy has been most successful in acute promyelocytic leukemia using all-trans-retinoic acid as the inducer, either alone or in combination with chemotherapy. This review presents evidence that a number of hematopoietic cytokines play important roles in both normal and aberrant hematopoietic processes. In vitro laboratory investigations in the past two decades using well-characterized myeloid leukemic cell lines and primary blast cells from leukemia patients have revealed that many hematopoietic cytokines can trigger lineage-specific differentiation of leukemia cells, which may have important implications in the clinical setting. Moreover, our current understanding of cytokine interactions and the molecular mechanisms of cytokine-induced leukemic cell differentiation will be discussed in the light of recent findings. Finally, ways in which laboratory research on cytokines in the differentiation therapy of leukemia can lead to the improved design of protocols for future clinical applications to leukemia therapy will also be addressed.
| Abbreviations | ||
| ALL, | = | acute lymphoblastic leukemia; |
| AML, | = | acute myeloid (or myelogenous) leukemia; |
| APC, | = | antigen-presenting cell; |
| APL, | = | acute promyelocytic leukemia; |
| As2 O3, | = | arsenic trioxide; |
| ATRA, | = | all-trans-retinoic acid; |
| BCR-ABL, | = | breakpoint cluster region-Abelson oncogene; |
| BFU-E, | = | erythroid burst-forming unit; |
| CDK, | = | cyclin-dependent kinase; |
| CFU-E, | = | erythroid colony-forming unit; |
| CLL, | = | chronic lymphoblastic leukemia; |
| CML, | = | chronic myeloid (or myelogenous) leukemia; |
| CSF, | = | colony-stimulating factor; |
| DC, | = | dendritic cell; |
| DMSO, | = | dimethylsulfoxide; |
| EBP, | = | enhancer-binding protein; |
| EPO, | = | erythropoietin; |
| EPOR, | = | erythropoietin receptor; |
| FAB, | = | French-American-British; |
| Flt-3, | = | Fms-like tyrosine kinase-3; |
| G-CSF, | = | granulocyte colony-stimulating factor; |
| GM-CSF, | = | granulocyte macrophage colony-stimulating factor; |
| HGF, | = | hematopoietic growth factor; |
| HLA, | = | human leukocyte antigen; |
| HSC, | = | hematopoietic stem cell; |
| HSCT, | = | hematopoietic stem cell transplantation; |
| IFN, | = | interferon; |
| IL, | = | interleukin; |
| JAK, | = | Janus kinase; |
| LAK, | = | lymphokine-activated killer; |
| LIF, | = | leukemia inhibitory factor; |
| LSC, | = | leukemia stem cell; |
| MAPK, | = | mitogen-activated protein kinase; |
| M-CSF, | = | macrophage colony-stimulating factor; |
| MHC, | = | major histocompatibility complex; |
| MIP-1α, | = | macrophage inflammatory protein-1α; |
| MPC, | = | myeloid progenitor cell; |
| NAP, | = | neutrophil alkaline phosphatase; |
| NK, | = | natural killer; |
| NKT, | = | natural killer T; |
| NOD, | = | non-obese diabetic; |
| PKC, | = | protein kinase C; |
| PKX, | = | protein kinase X; |
| PMA, | = | phorbol myristate acetate; |
| PML-RARα, | = | promyelocytic leukemia-retinoic acid receptorα; |
| RA, | = | retinoic acid; |
| RT-PCR, | = | reverse transcription polymerase chain reaction; |
| RXR, | = | retinoid X receptor; |
| SCF, | = | stem cell factor; |
| SCID, | = | severe combined immunodeficient; |
| SDF-1, | = | stromal cell derived factor-1; |
| STAT, | = | signal transducer and activator of transcription; |
| TGF-β, | = | transforming growth factor-β; |
| TNF-α, | = | tumor necrosis factor-α; |
| TPA, | = | 12-O-tetradecanoylphorbol-13-acetate; |
| TPO, | = | thrombopoietin; |
| VD3, | = | 1,25-dihydroxy vitamin D3; |
| VD3R, | = | 1,25-dihydroxy vitamin D3 receptor. |
| Abbreviations | ||
| ALL, | = | acute lymphoblastic leukemia; |
| AML, | = | acute myeloid (or myelogenous) leukemia; |
| APC, | = | antigen-presenting cell; |
| APL, | = | acute promyelocytic leukemia; |
| As2 O3, | = | arsenic trioxide; |
| ATRA, | = | all-trans-retinoic acid; |
| BCR-ABL, | = | breakpoint cluster region-Abelson oncogene; |
| BFU-E, | = | erythroid burst-forming unit; |
| CDK, | = | cyclin-dependent kinase; |
| CFU-E, | = | erythroid colony-forming unit; |
| CLL, | = | chronic lymphoblastic leukemia; |
| CML, | = | chronic myeloid (or myelogenous) leukemia; |
| CSF, | = | colony-stimulating factor; |
| DC, | = | dendritic cell; |
| DMSO, | = | dimethylsulfoxide; |
| EBP, | = | enhancer-binding protein; |
| EPO, | = | erythropoietin; |
| EPOR, | = | erythropoietin receptor; |
| FAB, | = | French-American-British; |
| Flt-3, | = | Fms-like tyrosine kinase-3; |
| G-CSF, | = | granulocyte colony-stimulating factor; |
| GM-CSF, | = | granulocyte macrophage colony-stimulating factor; |
| HGF, | = | hematopoietic growth factor; |
| HLA, | = | human leukocyte antigen; |
| HSC, | = | hematopoietic stem cell; |
| HSCT, | = | hematopoietic stem cell transplantation; |
| IFN, | = | interferon; |
| IL, | = | interleukin; |
| JAK, | = | Janus kinase; |
| LAK, | = | lymphokine-activated killer; |
| LIF, | = | leukemia inhibitory factor; |
| LSC, | = | leukemia stem cell; |
| MAPK, | = | mitogen-activated protein kinase; |
| M-CSF, | = | macrophage colony-stimulating factor; |
| MHC, | = | major histocompatibility complex; |
| MIP-1α, | = | macrophage inflammatory protein-1α; |
| MPC, | = | myeloid progenitor cell; |
| NAP, | = | neutrophil alkaline phosphatase; |
| NK, | = | natural killer; |
| NKT, | = | natural killer T; |
| NOD, | = | non-obese diabetic; |
| PKC, | = | protein kinase C; |
| PKX, | = | protein kinase X; |
| PMA, | = | phorbol myristate acetate; |
| PML-RARα, | = | promyelocytic leukemia-retinoic acid receptorα; |
| RA, | = | retinoic acid; |
| RT-PCR, | = | reverse transcription polymerase chain reaction; |
| RXR, | = | retinoid X receptor; |
| SCF, | = | stem cell factor; |
| SCID, | = | severe combined immunodeficient; |
| SDF-1, | = | stromal cell derived factor-1; |
| STAT, | = | signal transducer and activator of transcription; |
| TGF-β, | = | transforming growth factor-β; |
| TNF-α, | = | tumor necrosis factor-α; |
| TPA, | = | 12-O-tetradecanoylphorbol-13-acetate; |
| TPO, | = | thrombopoietin; |
| VD3, | = | 1,25-dihydroxy vitamin D3; |
| VD3R, | = | 1,25-dihydroxy vitamin D3 receptor. |