IRF4 Mediates the Oncogenic Effects of STAT3 in Anaplastic Large Cell Lymphomas

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.

The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL)

“…Recent studies have revealed interferon regulatory factor 4 ( IRF4 ) as a STAT3 key target gene, promoting survival of the neoplastic cells by activation of the transcription factor MYC. However, independently of IRF4 genetic alterations (translocations or overexpression), IRF4 has been shown to induce the survival of ALCL neoplastic cells [ 90 , 91 ]. In myeloma cells, this mechanism is described as an autoregulatory circuit, with IRF4 directly targeting MYC and at the same time IRF4 representing a direct target of MYC transactivation [ 92 ].…”

STAT3 Dysregulation in Mature T and NK Cell Lymphomas

“…Anaplastic large-cell lymphoma, ALK+ [22,[24][25][26][46][47][48][49][50][51][52][53][54][55][56][57][58][59] Anaplastic large-cell lymphoma, ALK− [22,25,46,52,56,[59][60][61] Breast Implant Associated anaplastic large-cell lymphoma [27,28,60] Angioimmunoblastic T cell lymphoma [22,46,62] Peripheral T cell lymphoma, NOS [22,46,63,64] T cell large granular Lymphocytic Leukemia [27,[30][31][32]46,65,66] NK/T cell lymphoma, nasal type and NK/T cell lymphoma [27,34,36,46,[67][68]…”

“…STAT3 also binds to and regulates the expression of interferon regulatory factor 4 (IRF4), a transcription factor important for promoting Th17 differentiation [21]. Chromatin immunoprecipitation revealed that STAT3 binds to the regulatory regions of IRF4 [58]. The STAT3 dependent expression of IRF4 appears to be involved in oncogenesis in ALK+ ALCL cells [58].…”

“…Chromatin immunoprecipitation revealed that STAT3 binds to the regulatory regions of IRF4 [58]. The STAT3 dependent expression of IRF4 appears to be involved in oncogenesis in ALK+ ALCL cells [58]. In ALCL cell lines, shRNA knockdown of IRF4 led to decreased cell survival, which was reversed by ectopic expression of IRF4.…”

“…Knockdown of STAT3 in cell lines also led to decreased IRF4 mRNA and protein expression. In ALCL cell lines with transduced IRF4, STAT3 knockdown led to decreased apoptosis, suggesting that IRF4 plays a role in the STAT3 mediated growth and survival of malignant cells [58]. In ALCL, IRF4 regulates Myc expression, which leads to increased pro-survival signals [59].…”