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Abstract

Over the past decade, there has been an exponential increase in our knowledge of how cytokines regulate signal transduction, cell cycle progression, differentiation and apoptosis. Research has focused on different biochemical and genetic aspects of these processes. Initially, cytokines were identified by clonogenic assays and purified by biochemical techniques. This soon led to the molecular cloning of the genes encoding the cytokines and their cognate receptors. Determining the structure and regulation of these genes in normal and malignant hematopoietic cells has furthered our understanding of neoplastic transformation. Furthermore, this has allowed the design of modified cytokines which are able to stimulate multiple receptors and be more effective in stimulating the repopulation of hematopoietic cells after myelosuppressive chemotherapy. The mechanisms by which cytokines transduce their regulatory signals have been evaluated by identifying the involvement of specific protein kinase cascades and their downstream transcription factor targets. The effects of cytokines on cell cycle regulatory molecules, which either promote or arrest cell cycle progression, have been more recently examined. In addition, the mechanisms by which cytokines regulate apoptotic proteins, which mediate survival vs death, are being elucidated. Identification and characterization of these complex, interconnected pathways has expanded our knowledge of leukemogenesis substantially. This information has the potential to guide the development of therapeutic drugs designed to target key intermediates in these pathways and effectively treat patients with leukemias and lymphomas. This review focuses on the current understanding of how hematopoietic cytokines such as IL-3, as well as its cognate receptor, are expressed and the mechanisms by which they transmit their growth regulatory signals. The effects of aberrant regulation of these molecules on signal transduction, cell cycle regulatory and apoptotic pathways in transformed hematopoietic cells are discussed. Finally, anti-neoplastic drugs that target crucial constituents in these pathways are evaluated.

De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes

“…Proliferation, leukocyte chemotaxis and regulation of the apoptotic threshold depend on appropriate signals through a favorable cytokine milieu for their homing to the bone marrow75767778. Our results suggest that IL-32 participates in the regulation of the bone marrow cytokine milieu, at least in part, through MAPK and NF-κB signaling.…”

Retargeted adenoviruses for radiation-guided gene delivery

“…36 , 37 Activated immediate-early genes interact with the promoter region of the so-called late-responding genes, coding for cytokines, involved in the inflammation process (for example, IL-6), and growth factors, involved in cell survival (for example, TGFβ1, TNF-α). 38 , 39 , 40 Thus, the promoters from many stress response genes related to cellular fate following DNA damage are potential candidates for cancer gene therapy. At present, several radiation-inducible promoters including Egr-1, 41 , 42 , 43 tPA, 44 p21/WAF-1 45 and GADD45α 46 , 47 were used for gene delivery in combination with radiation therapy strategies.…”

Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia

“…CD123 is expressed on myeloid progenitors, plasmacytoid dendritic cells, monocytes and basophils [45]. Binding of IL-3 triggers CD123 hetero-dimerization with the β-subunit shared by the granulocyte macrophage-colony-stimulating-factor and IL5 receptor complex inducing hematopoietic progenitor cell differentiation and proliferation by phosphorylation of Janus kinase, activation of PI3 kinase and upregulation of anti-apoptotic proteins [46, 47]. CD123 was initially described as a putative marker of leukemic stem cells with increased expression in the CD34+/CD38- primitive leukemic blasts which contained the NSG repopulating activity of AML samples [48].…”