In this report, we provide evidence that IRF4 functions as a tumor suppressor in c-Myc induced B cell leukemia. Our results show that c-Myc induced leukemia was dramatically accelerated in IRF4+/−Myc mice. Moreover, five out of six of IRF4+/−Myc leukemic clones further inactivated the remaining wild type IRF4 allele, resulting in a complete loss of IRF4 expression in those cells. Our finding is consistent with a previous study which shows that IRF4 functions as tumor suppressor in BCR/ABL oncogene induced B-ALL and further demonstrates that IRF4 is capable of functioning as a tumor suppressor against a broad spectrum of oncogene insults at the pre-B stage. The accelerated leukemogenesis in the IRF4+/−Myc mice can be caused by defect in pre-B cell development. Progenitor B cells are expanded in wild type EμMyc mice. As IRF4 is a critical regulator of pre-B cell differentiation, loss of IRF4 expression can further exacerbate the defect in early B cell development in the EμMyc mice, causing further expansion of progenitor B cells pool that could serve as targets for subsequent transformation.
C-Myc induced leukemia and lymphoma is held in check by p27kip
which inhibit cell cycle progression and by the Arf-p53 pathway that promotes apoptosis 
. However, the frequency of p53 mutation in the IRF4+/−
Myc leukemic cells is similar to wild type EμMyc cells, suggesting that accelerated leukemogenesis in IRF4+/−
Myc mice isn't a result of high frequency of p53 mutation. Instead, our results indicate that deficiency of IRF4 accelerates the loss of p27kip
in c-Myc overexpressing cells. First, the expanded B220+IgM-cells in IRF4+/−
Myc mice lost the expression of p27kip
and were hyperproliferative; second, reconstitution of IRF4 expression in IRF4+/−
Myc leukemic cells induced the expression of p27kip
and inhibited their proliferation. It has been shown that Ikaros can induce the expression p27kip
in leukemic cells 
. As expression of Ikaros is induced by IRF4, it is possible that the induction of p27kip
expression could be mediated by Ikaros. It is also possible that loss of IRF4 expression somehow accelerates the loss of p27kip
in c-Myc overexpressing cells through mechanisms independent of Ikaros.
Pre-B cell receptor signaling has been proposed as a guardian of pre-B cell transformation by coordinating pre-B cell expansion and differentiation. IRF4 expression is dependent on pre-BCR signaling which is transduced by downstream signaling molecules such as Blnk, Btk and PLCγ2. Moreover, previous studies have identified Btk, Blnk and PLCγ2 as potential tumor suppressors against pre-B cell transformation 
. Interestingly, a previous study has shown that c-Myc induced leukemia/lymphoma is accelerated in PLCγ2 deficient mice (PLCγ2−/−
. Similar to IRF4, PLCγ2 is critical for pre-B cell development and in its absence, pre-B cell development is partially blocked, resulting in an expansion of pre-B cells. Interestingly, like IRF4+/−
Myc leukemic cells, PLCγ2−/−
Myc tumor cells lost the expression of p27kip
and didn't exhibit enhanced frequency of p53 mutation 
. However, PLCγ2 does not behave like classical tumor suppressor as c-Myc induced leukemogenesis remains unaltered in the PLCγ2+/−
Myc mice. In contrast, our results show that IRF4 behaves like a classical tumor suppressor, downstream of pre-BCR signaling, that functions to inhibit c-Myc induced leukemia.