The recent identification of germline and somatic mutations in BAP1 as well as 
in multiple members of the ASXL (additional sex combs-like) family of genes has 
highlighted the role of these proteins in a diverse array of biological 
functions. A diverse number of possible functions have previously been ascribed 
to ASXL1 in non-hematopoietic contexts, including physical co-operativity with 
HP1a and LSD1. Here we discuss new evidence for a BAP1-independent function of 
ASXL1 in regulating histone H3 lysine 27 methylation through interactions with 
the Polycomb-repressive complex 2 (PRC2). BAP1, a nuclear-localized 
deubiquitinase, has been shown to interact with a number of proteins, including 
ASXL1 and/or ASXL2, but the functional importance of this interaction has 
remained elusive. Here, we highlight recent work revealing the critical function 
of BAP1 in restricting myelopoiesis and in regulating hematopoietic stem cell 
function. These data provide evidence that BAP1 and ASXL1 function as a novel 
class of tumor suppressors in myeloid malignancies. BAP1 functions through 
effects on stability of host cell factor-1, and O-GlcNAcylation, and ASXL1 
impacts histone post-translational modifications through interaction with PRC2. 
Future studies investigating the mechanism of transformation by loss of BAP1 and 
ASXL1 may result in new therapeutic approaches to treat hematological 
malignancies.