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Review
. 2012 Apr 20;36(4):529-41.
doi: 10.1016/j.immuni.2012.03.017.

Janus kinase deregulation in leukemia and lymphoma

Edwin Chen  1 , Louis M Staudt, Anthony R Green
Affiliations
Review

Janus kinase deregulation in leukemia and lymphoma

Edwin Chen et al. Immunity. .

Abstract

Genetic alterations affecting members of the Janus kinase (JAK) family have been discovered in a wide array of cancers and are particularly prominent in hematological malignancies. In this review, we focus on the role of such lesions in both myeloid and lymphoid tumors. Oncogenic JAK molecules can activate a myriad of canonical downstream signaling pathways as well as directly interact with chromatin in noncanonical processes, the interplay of which results in a plethora of diverse biological consequences. Deciphering these complexities is shedding unexpected light on fundamental cellular mechanisms and will also be important for improved diagnosis, identification of new therapeutic targets, and the development of stratified approaches to therapy.

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Figures

Figure 1.
Figure 1.. Summary of JAK Mutations Discovered in Hematological Malignancies
Color-coded representation of the location of each mutant residue within the domain structure of each JAK protein. The majority of mutations in JAK proteins are found within the pseudokinase or kinase domain.
Figure 2.
Figure 2.. Signaling Complexities of Janus Kinases
Janus kinases (JAKs) such as JAK2 can modulate signaling through multiple different cytokine receptor families, and can activate multiple downstream canonical pathways such as STATs, PI3K and ERK, as well as non-canonical pathways via direct nuclear targeting. The biological consequences elicited by oncogenic JAK signaling will therefore depend on the complement of receptors, STATs and other signaling pathway components present in that cellular context.
Figure 3.
Figure 3.. JAK-STAT Signaling in Lymphomas
Top: Autocrine JAK-STAT3 signaling in activated B cell like diffuse large B cell lymphoma. MYD88 mutants activate NF-κB and p38 MAP kinase signaling pathways to increase production and secretion of IL-6 and IL-10, which in turn activate the JAK-STAT3 pathway by autocrine stimulation of their respective receptors. MYD88 mutants can also activate type I interferon pathways through increased production of IFN-β. Bottom, Molecular consequences of 9p24 amplification in Hodgkin lymphoma and primary mediastinal B cell lymphoma. Increased expression of JAK2 and JMJD2C following 9p24 amplification synergizes to destabilize heterochromatic state and positively regulate expression of multiple genes (such as those encoding MYC, JAK2, JMJD2C, IL4RA, PD-L1, and PD-L2) that promote increased growth factor signaling, immune suppression and proliferation.
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