Nanoparticle delivery of inhibitory signal transducer and activator of transcription 3 G-quartet oligonucleotides blocks tumor growth in HMGA1 transgenic model of T-cell leukemia

摘要

While survival from childhood acute lymphoblastic leukemia (ALL) has improved significantly over the past three decades, pediatric patients with T-cell ALL (T-ALL) remain at high risk for relapse and poor outcomes compared to children with B-cell precursor ALL [1-3]. Outcomes for adults with T-ALL are even worse, with long-term survival rates of only 30-40% in patients less than 60 years, which falls to 10% in patients over 60 years [1-3]. Thus, studies are urgently needed to identify key molecular pathways that could be targeted in therapy. Similar to other malignancies, oncogene activation by mutation or overexpression is common in T-ALL. For example, overexpression of the TAL-1 oncogene occurs in most cases of pediatric T-ALL [2-4]. We discovered that the high mobility group Al (HMGA1) oncogene is also overex-pressed in T-ALL [1]. Activating mutations in other onco-genes have been identified, including LM02, TLX1/HOX1, TLX3/HOX11L2 and HOXA, which appear to specify distinct T-ALL subtypes [1-3]. Other recurrent mutations in T-ALL include chromosomal loss of the CDKN2A/B tumor suppressor loci or activating mutations in the NOTCH1 pathway that occur in most subtypes of T-ALL [1-3]. NKX2-1 and MEF2C are putative oncogenes found in T-ALL subtypes that lack known oncogenic rearrangements [4].