Leukemia stem cells (LSC) play a pivotal role in chronic myeloid leukemia (CML) tyrosine kinase inhibitor (TKI) resistance and progression to blast crisis (BC), in part, through alternative splicing of self-renewal and survival genes. inhibition of pro-survival BCL2 family proteins and buy Hydroxyflutamide BCR-ABL may eliminate dormant LSC and obviate resistance. Introduction Human leukemia stem cells (LSC), first described in acute myeloid leukemia (AML) (Lapidot et al., 1994), subvert stem cell properties, such as quiescence, enhanced self-renewal and survival, which render them resistant to conventional therapy (Guzman et al., 2002; Visvader, 2011). Chronic myeloid leukemia (CML) represents an important paradigm for dissecting the molecular evolution of LSC during leukemic progression and the role of LSC in therapeutic resistance because CML was the first malignancy to be targeted with therapy that selectively inhibits the aberrant kinase responsible for CML initiation (Druker et al., 2001). Although BCR-ABL-targeted tyrosine kinase inhibitors (TKIs) eradicate the bulk of BCR-ABL1 expressing cells, they frequently fail to eliminate quiescent, niche-resident LSC that drive relapse (Abe et al., 2008; Barnes and Melo, 2006; Chomel et al., 2011; Corbin et al., 2011) and blast buy Hydroxyflutamide crisis (BC) transformation following TKI discontinuation (Chomel and Turhan, 2011; Cortes et al., 2004; Deininger, 2008; Stuart et al., 2009). Despite improved overall survival (Druker et al., 2006), no curative pharmacologic therapy for CML exists, in part, because the genetic and epigenetic drivers of human BC LSC generation remain to be elucidated. In human BC CML and in many cases of AML, LSC are enriched within the CD34+CD38+Lin? compartment, which is composed predominantly of granulocyte-macrophage progenitors (GMP) (Eppert et al., 2011; Goardon et al., 2011; Jamieson et al., 2004) with aberrant self-renewal capacity. Serial transplantation experiments show that as few as 1,000 GMP serially transplant human BC CML (Abrahamsson et al., 2009). Moreover, GMP LSC have been identified in transgenic mouse models of both BC CML (Jaiswal et al., 2003) and of AML (Krivtsov et al., 2006) suggesting that malignant transformation of progenitors into LSC, through aberrant acquisition of stem cell properties, is a key driver of leukemic progression. Evidence from primary patient samples demonstrates that chronic phase (CP) CML is a clonal disorder (Martin et al., 1980) that originates from BCR-ABL (Daley et al., 1990) expressing hematopoietic stem cells (HSC) (Jamieson et al., 2004). Although necessary for CP initiation, BCR-ABL expression is not sufficient to drive BC transformation (Radich et al., 2006). Both mouse transgenic model and xenotransplantation data show that activation of stem cell signaling pathways, including WNT/-catenin (Abrahamsson et al., 2009; Jamieson et al., 2004; McWeeney et al., 2009; Zhao et al., 2007), Hedgehog (Zhao et al., 2009) and the intrinsic apoptotic pathway regulated by the BCL2 gene family (Jaiswal et al., 2003), promote BC transformation. Malignant transformation of BCR-ABL1 expressing GMP into self-renewing BC LSC (CD34+CD38+Lin?) occurs, in some cases, as a consequence of alternative splicing of GSK3, a negative regulator of Wnt/-catenin, Hedgehog signaling and MCL1 (Abrahamsson et al., 2009; Ding et al., 2007). While recent reports reveal that mutations in splicing genes promote progression of myeloid malignancies to acute leukemia (Yoshida et al., 2011), alternative splicing-mediated alterations in the transcriptome may also enable BC transformation in a malignant microenvironment. Because CML becomes increasingly refractory to TKIs during progression to BC (Karbasian Esfahani et al., 2006; Sawyers et al., 2002), understanding the epigenetic mechanisms that drive BC LSC buy Hydroxyflutamide maintenance and contribute to therapeutic resistance is Rabbit polyclonal to AFG3L1 essential. In addition, several studies suggest that LSC quiescence induction by the stem cell niche is a major component of therapeutic resistance (Barnes and Melo, 2006; Corbin et al., 2011; Forsberg et al., 2010; Holyoake et al., 1999; Saito et al., 2010). Although, recent evidence shows that increased.