IRF4 in multiple myeloma
IRF4 is a
transcription factor that is required at different stages of B cell development
and, in particular, in the differentiation of B cells into plasma cells. In many
MM, the malignant plasma cells are dependent on IRF4 for maintenance and survival despite the fact that the gene is
not always mutated to an oncogenic form [17]. Hence
this dependency is termed non-oncogene dependency. IRF4 is of notable significance because current treatments for MM
are ineffective and the median survival time is only 3-4 years following
initial treatment [43].
IRF4 is expressed in
acutely activated B cells, and directs them to terminally differentiate into
plasma cells by acting as a positive transcriptional regulator of genes
involved in differentiation and proliferation. As many as 308 genes are direct
or indirect targets of IRF4, of which 101 have been shown to be upregulated in MM
cell lines [17]. This
broad regulation stems from the fact that IRF4 is at the apex in the hierarchy
of gene regulators in that it regulates expression of other transcription
factors which then further regulate gene expression. Moreover MYC, one transcription
factor upregulated by IRF4, is a direct positive regulator of IRF4 itself [17]. Thus,
IRF4 may act in a positive feedback loop to maintain its own expression whilst
driving cancer progression.
Dependence of MM on
non-oncogenic IRF4 was demonstrated using short hairpin RNA (shRNA) screens
with retroviral expression vectors [17].
Retroviruses carrying different shRNAs were transfected into MM cell lines and
shRNA expression was induced by addition of doxycycline. Several shRNAs
targeting IRF4 were identified that
were able to kill ten different cell lines, each with a distinct molecular manifestation
of MM. One particular shRNA targeting the 3’ untranslated region of IRF4 mRNA
reduced its expression by 50-75%, and killed MM cells within 3 days.
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