BIRC6 (APOLLON) is down-regulated in acute myeloid leukemia and its knockdown attenuates neutrophil differentiation

We found significantly lower BIRC6 levels in particular AML subtypes as compared to granulocytes from healthy donors. The lowest BIRC6 expression was found in CD34+ progenitor cells. Moreover, BIRC6 expression significantly increased during neutrophil differentiation of AML cell lines and knocking down BIRC6 in NB4 acute promyelocytic leukemia (APL) cells significantly impaired neutrophil differentiation, but not cell viability.Together, we found an association of low BIRC6 levels with an immature myeloid phenotype and describe a function for BIRC6 in neutrophil differentiation of APL cells.BIRC6 (a.k.a. APOLLON, BRUCE) is an exceptionally large protein of 528？kDa belonging to the family of inhibitor of apoptosis (IAP). BIRC6 contains one bacalovirus IAP repeat (BIR) domain that shows homology to the IAP Survivin. Furthermore, BIRC6 is the only IAP with an ubiquitin-conjugating domain further pointing to a particular function of this protein in the IAP family [1]. Several groups reported that BIRC6 executes its function via inhibition of Smac and Caspase-9[2,3]. Moreover, a study in breast cancer cells revealed that BIRC6 inhibits cell death by p53 destabilization and inactivation of caspase-3[4]. The role of p53-dependent BIRC6 effector functions was confirmed by investigations of Ren et al. in mice and human lung cancer cells [5].Due to their anti-apoptotic function it was hypothesized that overexpression of IAPs might contribute to tumorigenesis. Survivin, for example, one of the best studied IAPs is up regulated in most tumors and has been associated with their chemoresistence [6,7]. Recently, Houdt et al. [8] observed BIRC6 overexpression in colon cancer stem cells when compared to more differentiated tumor cells. BIRC6 expression protected colon cancer stem cells from the cytotoxic effects of oxaliplatin and cisplatin. Furthermore, knocking-down BIRC6 led to growth inhibition in several cancer cell lines and xenografted mice and rendered the tumor cells more s