3 B; P 0.0001 vs. pathways drive disease progression and provide potential targets for novel therapeutic IMD 0354 strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of IMD 0354 candidate therapies to improve the dismal outcomes in this highly aggressive disease. Chronic myeloid leukemia (CML) is a chronic myeloproliferative neoplasm, resulting from a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11). This lesion was the first recurrent chromosomal abnormality described in cancer (Nowell and Hungerford, 1960; Rowley, 1973) and generates the BCR-ABL oncoprotein, a constitutively activated protein tyrosine kinase (TK; Deininger et al., 2000). Mouse models and human data have demonstrated BCR-ABL expression to be causative in CML (Daley et al., 1990; Heisterkamp et al., 1990; Zhao et al., 2001; Ramaraj et al., 2004; Koschmieder et al., 2005), and this observation has led to the paradigmic development of potent small molecule inhibitors that selectively target ABL enzymatic function and interrupt its oncogenic TK activity. Imatinib mesylate, the prototypic ABL tyrosine kinase inhibitor (TKI), and subsequent second and third generation TKIs, have revolutionized CML treatment (Druker et al., 1996; 2006; Carroll et al., 1997; Heinrich et al., 2000; OBrien et al., 2003), significantly improving cytogenetic and molecular response rates, keeping the majority of patients in chronic phase, and prolonging overall survival (Druker et al., 2001, 2006; Sawyers et al., 2002; Hughes et al., 2003). However, despite this vast improvement, significant clinical challenges still remain in CML therapy. CML stem cells appear relatively resistant to the effects of TKIs (Copland et al., 2006; J?rgensen et al., 2007; Konig et al., 2008) such that, in the majority of patients, CML is controlled rather than cured. In addition, resistance occurs and this, together with stem cell persistence, facilitates disease transformation. Three distinct phases of the disease have been described. The initial phase, in which 85C90% of patients are diagnosed, is the indolent chronic phase (CP), which is readily amenable to treatment. However, without adequate therapy, this almost inevitably progresses to an aggressive acute leukemia of myeloid or lymphoid phenotype (70 and 30%, respectively), termed blast crisis (BC), which may be preceded by an ill-defined intermediate or accelerated phase (AP; during which the levels of myeloblasts in the BM or peripheral blood (PB) are increased but remain 20%). 10C15% of patients present beyond CP and a small percentage of CP cases continue to transform even on TKI therapy. The frequency of transformation is recorded at 3C5% within the first few years of TKI therapy but drops to 1% per year thereafter in randomized trials (Druker et al., 2006), although these values have been found to be higher in population-based studies (de Lavallade et al., 2008; Gallipoli et al., 2011). Treatment options for AP and BC are very limited, with response rates to TKIs lower and much less durable. Other options involve highly toxic therapies, such as combination chemotherapy and BM transplantation, and are not available or appropriate for many patients with progression. Therefore, even in the TKI era, the median survival of patients with BC is still dismal at around 6 mo (Hehlmann and Saussele, 2008; Silver et al., 2009), defining it as an unmet clinical need. Although the chronic phase of CML appears almost entirely dependent on BCR-ABL and CML is regarded as an invaluable model of leukemic evolution, the molecular mechanisms underlying disease progression are still poorly annotated. It is generally accepted that additional mutations cooperate with BCR-ABL during progression to BC (Calabretta.Three distinct phases of the disease have been described. phenotype, cellular and molecular biology of human CML progression. We report a heterogeneous and unique pattern of insertions identifying known and novel candidate genes and demonstrate that these pathways drive disease progression and provide potential targets for novel therapeutic strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of candidate therapies to improve the dismal outcomes in this highly aggressive disease. Chronic myeloid leukemia (CML) is a chronic myeloproliferative neoplasm, resulting from a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11). This Rabbit Polyclonal to TNFRSF6B lesion was the first recurrent chromosomal abnormality described in cancer (Nowell and Hungerford, 1960; Rowley, 1973) and generates the BCR-ABL oncoprotein, a constitutively activated protein tyrosine kinase (TK; Deininger et al., 2000). Mouse models and human data have demonstrated BCR-ABL expression to be causative in CML (Daley et al., 1990; Heisterkamp et al., 1990; Zhao et al., 2001; Ramaraj et al., 2004; Koschmieder et al., 2005), and this observation has led to the paradigmic development of potent small molecule inhibitors that selectively target ABL enzymatic function and interrupt its oncogenic TK activity. Imatinib mesylate, the prototypic ABL tyrosine kinase inhibitor (TKI), and subsequent second and third generation TKIs, have revolutionized CML treatment (Druker et al., 1996; 2006; Carroll et al., 1997; Heinrich et al., 2000; OBrien et al., 2003), significantly improving cytogenetic and molecular response rates, keeping the majority of individuals in chronic phase, and prolonging overall survival (Druker et al., 2001, 2006; Sawyers et al., 2002; Hughes et al., 2003). However, despite this vast improvement, significant medical challenges still remain in CML therapy. CML stem cells appear relatively resistant to the effects of TKIs (Copland et al., 2006; J?rgensen et al., 2007; Konig et al., 2008) such that, in the majority of individuals, CML is controlled rather than cured. In addition, resistance occurs and this, together with stem cell persistence, facilitates disease transformation. Three distinct phases of the disease have been explained. The initial phase, in which 85C90% of individuals are diagnosed, is the indolent chronic phase (CP), which is definitely readily amenable to treatment. However, without adequate therapy, this almost inevitably progresses to an aggressive acute leukemia of myeloid or lymphoid phenotype (70 and 30%, respectively), termed blast problems (BC), which may be preceded by an ill-defined intermediate or accelerated phase (AP; during which the levels of myeloblasts in the BM or peripheral blood (PB) are improved but remain 20%). 10C15% of individuals present beyond CP and a small percentage of CP instances continue to transform actually on TKI therapy. The rate of recurrence of transformation is definitely recorded at 3C5% within the first few years of TKI therapy but drops to 1% per year thereafter in randomized tests (Druker et al., 2006), although these ideals have been found out to be higher in population-based studies (de Lavallade et IMD 0354 al., 2008; Gallipoli et al., 2011). Treatment options for AP and BC are very limited, with response rates to TKIs lower and much less durable. Other options involve highly toxic therapies, such as combination chemotherapy and BM transplantation, and are not available or appropriate for many individuals with progression. Consequently, actually in the TKI era, the median survival of individuals with BC is still dismal at around 6 mo (Hehlmann and Saussele, 2008; Metallic et al., 2009), defining it as an unmet medical need. Even though chronic phase of CML appears almost entirely dependent on BCR-ABL and CML is regarded as an invaluable model of leukemic development, the molecular.