Abstract
Systemic anaplastic large cell lymphomas (ALCL) are a category of T-cell non-Hodgkin’s lymphomas which can be divided into anaplastic lymphoma kinase (ALK) positive and ALK negative subgroups, based on ALK gene rearrangements. Among several pathways aberrantly activated in ALCL, the constitutive activation of signal transducer and activator of transcription 3 (STAT3) is shared by all ALK positive ALCL and has been detected in a subgroup of ALK negative ALCL. To discover essential mediators of STAT3 oncogenic activity that may represent feasible targets for ALCL therapies, we combined gene expression profiling analysis and RNA interference functional approaches. A shRNA screening of STAT3-modulated genes identified interferon regulatory factor 4 (IRF4) as a key driver of ALCL cell survival. Accordingly, ectopic IRF4 expression partially rescued STAT3 knock-down effects. Treatment with immunomodulatory drugs (IMiDs) induced IRF4 down regulation and resulted in cell death, a phenotype rescued by IRF4 overexpression. However, the majority of ALCL cell lines were poorly responsive to IMiDs treatment. Combination with JQ1, a bromodomain and extra-terminal (BET) family antagonist known to inhibit MYC and IRF4, increased sensitivity to IMiDs. Overall, these results show that IRF4 is involved in STAT3-oncogenic signaling and its inhibition provides alternative avenues for the design of novel/combination therapies of ALCL.
Highlights
Systemic anaplastic large cell lymphomas (ALCL) are a rare type of T-cell lymphoma comprising a histologically heterogeneous group of hematopoietic neoplasms, often characterized by large cells with variable shape, consistently expressing the CD30 antigen [1]
Among early-regulated genes carrying conserved signal transducer and activator of transcription 3 (STAT3) binding sites (BS) in their regulatory regions, we found that Interferon Regulatory Factor 4 (IRF4) is a key protein involved in ALCL proliferation and survival
The constitutive activation of STAT3 is pathognomonic of anaplastic lymphoma kinase (ALK) positive ALCL and it is detectable in ~50% ALK negative ALCL, as a consequence of JAK1/STAT3 mutations or aberrant cytokine receptor signalling [21]
Summary
Systemic anaplastic large cell lymphomas (ALCL) are a rare type of T-cell lymphoma comprising a histologically heterogeneous group of hematopoietic neoplasms, often characterized by large cells with variable shape (anaplastic pattern), consistently expressing the CD30 antigen [1]. Since the discovery of ALK translocations in ALK-positive ALCL, a variety of mechanisms leading to aberrant/ectopic ALK signaling in several human cancers have been characterized These include translocations or structural rearrangements, mutations, gene amplification, and alternative transcription start sites [7,8]. Among early-regulated genes carrying conserved STAT3 binding sites (BS) in their regulatory regions, we found that Interferon Regulatory Factor 4 (IRF4) is a key protein involved in ALCL proliferation and survival. Overall, these findings show that IRF4 is involved in STAT3-oncogenic signaling, and that its inhibition might represent a promising avenue for the design of combination therapies in ALCL
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