Mutant IL-7Rα and mutant NRas are sufficient to induce murine T cell acute lymphoblastic leukemia
Mutant IL-7Rα and mutant NRas are sufficient to induce murine T cell acute lymphoblastic leukemia
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DOI：
10.1038/s41375-017-0001-0
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发表时间：
2018-08-01
期刊：
影响因子：
11.4
通讯作者：
Durum, Scott K.
中科院分区：
文献类型：
--
作者：
Cramer, Sarah D.;Hixon, Julie A.;Durum, Scott K.
Acute lymphoblastic leukemia (ALL) is the most common cancer of children, and current pediatric treatment protocols have resulted in 5-year overall survival rates up to 90%[1]. However, treatments often cause severe side effects [2]. In addition, relapsed pediatric patients have significantly reduced survival [2]. To address these issues, targeted therapies must be developed that are tailored to each individual case of ALL [3]. There are multiple potential therapeutic targets within pediatric ALL, but the IL-7Rα signaling pathways are particularly attractive. These pathways harbor genetic mutations at multiple signaling nodes in T-ALL and B-ALL [4]. Also, mutations of the IL-7Rα chain itself occur in~ 10% of pediatric T-ALL cases [4]. These mutations enable homodimerization of IL-7Rα and lead to constitutive signaling, enabling increased cell survival and proliferation [5]. However, experiments in our lab showed that mutation of IL-7Rα alone was insufficient to cause transformation of primary T cells (W Li and SK Durum, unpublished results). We hypothesized that additional genetic lesions must collaborate with mutated IL-7Rα or its signaling pathway members to cause leukemia. Pediatric patient data suggested at least three potential collaborative candidates: TLX3 (HOX11L2) expression, HOXA gene cluster overexpression, and mutations in NRAS and/or genes in its oncogenic pathways, the Raf/MEK/ERK and PI3K/Akt/mTOR pathways [5, 6]. These were considered potential collaborators because patients with mutated IL-7Rα were more likely to have TLX3 or HOXA subgroup leukemia [5]. In addition, concurrent genetic mutations in IL-7Rα and NRAS signaling pathways were quite common. For example, 10/24 T-ALL patients with NRAS/KRAS/NF1 pathway mutations and 13/37 Philadelphia chromosome-like BCP-ALL patients with NRAS pathway mutations had concurrent mutations in the IL-7Rα pathway [7, 8]. Concurrent NRAS and IL-7Rα pathway mutations also occurred in early T cell precursor leukemia and the T-ALL cell line DND41 [9, 10]. To assess these potential mutant IL-7Rα collaborations, we retrovirally transduced primary immature (CD4− CD8−) murine thymocytes, then injected these cells via tail vein into sub-lethally irradiated, 6–12-week-old, male and female Rag1−/−(B6. 129S7-Rag1tm1Mom/J) mice, a strain
