Cytokines in the Differentiation Therapy of Leukemia: From Laboratory Investigations to Clinical Applications

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.

Monitoring dendritic cell and cytokine biomarkers during remission prior to relapse in patients with FLT3-ITD acute myeloid leukemia

“…IL-6 was defined as a crucial factor for tumor survival and immune evasion, i.e., via induced secretion of IL-10 by regulatory T cells, which effectively suppresses adaptive immune responses towards tumor antigens [33] and induces proliferation of immature myeloid cells [34]. The combination of IL-6 and its inducers TNF-α and IL-1β [35] promotes tumor growth and survival in cancer patients through maintenance of chronic inflammation and induction of a tumor-supporting microenvironment [19, 36].…”

Differentiation therapy of leukemia: 3 decades of development

“…111 Some of the hematopoietic leukemia cell lines of myeloid origin such as K562, U937, HL-60, CS-1, KG-1, MUTZ-3, or ex vivo AML or chronic myeloid leukemia (CML) blasts were modestly permissive to induction of in vitro differentiation by EPO, G-CSF, GM-CSF, IL-4, IL-6, SCF, or synergistic combinations of several cytokines. [111][112][113][114][115] Molecular mechanisms of cytokineinduced leukemic differentiation were also elucidated. Several prominent proto-oncogenes such as c-myb, c-myc, c-fos, and Ets family transcription factors such as ets-1, fli-1, and TEL2 were found to be differentially regulated upon cytokine-induced differentiation of leukemic cells.…”

Pharmacogenomics and the Yin/Yang actions of ginseng: anti-tumor, angiomodulating and steroid-like activities of ginsenosides

“…Active growth of tumor cells can also be attenuated by induction of terminal differentiation and this approach has been developed as one of the strategies in cancer treatment [96]. Previously, Zeng and Tu showed that Rh 2 -treated hepatocarcinoma (SMMC-7721) cells exhibited the morphological characteristics of mature cells.…”