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Advances in the design of targeted therapies for the treatment of chronic myeloid leukemia (CML) have transformed the prognosis for patients diagnosed with this disease. However, leukemic stem cell persistence, drug intolerance, drug resistance, and advanced-phase disease represent unmet clinical needs demanding the attention of CML investigators worldwide. The availability of appropriate preclinical models is essential to efficiently translate findings from the bench to the clinic. Here we review the current approaches taken to preclinical work in the CML field, including examples of commonly used in vivo models and recent successes from systems biology-based methodologies. [ABSTRACT FROM AUTHOR]

Summary Expression of the initiator methionine tRNA (tRNA i Met ) is deregulated in cancer. Despite this fact, it is not currently known how tRNA i Met expression levels influence tumor progression. We have found that tRNA i Met expression is increased in carcinoma-associated fibroblasts, implicating deregulated expression of tRNA i Met in the tumor stroma as a possible contributor to tumor progression. To investigate how elevated stromal tRNA i Met contributes to tumor progression, we generated a mouse expressing additional copies of the tRNA i Met gene (2+tRNA i Met mouse). Growth and vascularization of subcutaneous tumor allografts was enhanced in 2+tRNA i Met mice compared with wild-type littermate controls. Extracellular matrix (ECM) deposited by fibroblasts from 2+tRNA i Met mice supported enhanced endothelial cell and fibroblast migration. SILAC mass spectrometry indicated that elevated expression of tRNA i Met significantly increased synthesis and secretion of certain types of collagen, in particular type II collagen. Suppression of type II collagen opposed the ability of tRNA i Met -overexpressing fibroblasts to deposit pro-migratory ECM. We used the prolyl hydroxylase inhibitor ethyl-3,4-dihydroxybenzoate (DHB) to determine whether collagen synthesis contributes to the tRNA i Met -driven pro-tumorigenic stroma in vivo. DHB had no effect on the growth of syngeneic allografts in wild-type mice but opposed the ability of 2+tRNA i Met mice to support increased angiogenesis and tumor growth. Finally, collagen II expression predicts poor prognosis in high-grade serous ovarian carcinoma. Taken together, these data indicate that increased tRNA i Met levels contribute to tumor progression by enhancing the ability of stromal fibroblasts to synthesize and secrete a type II collagen-rich ECM that supports endothelial cell migration and angiogenesis. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) stem/progenitor cells (SPCs) express a transcriptional program characteristic of proliferation, yet can achieve and maintain quiescence. Understanding the mechanisms by which leukemic SPCs maintain quiescence will help to clarify how they persist during long-term targeted treatment. We have identified a novel BCR-ABL1 protein kinase-dependent pathway mediated by the upregulation of hsa-mir183, the downregulation of its direct target early growth response 1 (EGR1), and, as a consequence, upregulation of E2F1. We show here that inhibition of hsa-mir183 reduced proliferation and impaired colony formation of CML SPCs. Downstream of this, inhibition of E2F1 also reduced proliferation of CML SPCs, leading to p53-mediated apoptosis. In addition, we demonstrate that E2F1 plays a pivotal role in regulating CML SPC proliferation status. Thus, for the first time, we highlight the mechanism of hsa-mir183/EGR1-mediated E2F1 regulation and demonstrate this axis as a novel, critical factor for CML SPC survival, offering new insights into leukemic stem cell eradication. [ABSTRACT FROM AUTHOR]