Implications Of Aberrant Jak Activation In Hematological Diseases

The essential role that JAKs play in normal hematopoietic regulation has been shown by gene-targeting studies that have identified characteristic signaling defects. JAK1 and JAK2 knockout mice are perinatal or embryonic lethal, whereas JAK3 nullizygous mice show severe combined immunodeficiency (SCID) (Table 1) (described in more detail in refs. 9 and 62). Consequently, inappropriate inhibition or absence of JAK activity causes immunosuppressive diseases. The prominent example is the presence of mutations in the JAK3 gene that leads to SCID in humans, characterized by an absence of peripheral T- and natural-killer cells and normal or slightly increased numbers of B-cells (63-66). Other heritable human diseases caused by intrinsic inactivating defects in JAKs have not been reported. However, a variety of pathogens, such as human papilloma virus or cytomegalovirus, are able to inhibit JAK-mediated IFN signaling, thereby escaping immunosurveillance (7,67,68).

On the other hand, constitutive or enhanced activation of JAK activity can result in malignant cell growth or even neoplastic transformation. The earliest evidence came from studies in nonhuman experimental systems. An amino acid substitution in the JAK homolog of Drosophila, HOP, owing to a point mutation in the hopscotch gene, was shown to produce a hyperactive kinase and caused leukemia-like abnormalities (69,70). Elevated JAK activity has also been implicated in an increasing number of human hematological malignancies (Table 2) (7,62,71,72). The mechanisms that may lead to increased JAK activation include intrinsic genetic defects like chromosomal translocations and gene amplification, phosphorylation by oncogenic tyrosine kinases, increased cytokine/growth factor production (either autocrine or paracrine), and disruption of normal negative regulation. So far, activating mutations resembling those in the Drosophila JAK homolog have not been found in human JAKs (73). The consequences of elevated JAK activity are numerous, reflecting the pleiotropic biological activities of cytokines and growth factors, and they depend on the signal transduction pathways that are initiated in the given cellular context. Mainly, aberrant JAK activity delivers increased proliferation and survival signals and thereby contributes to the process of malignant transformation.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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