Department of Pediatrics, University of California, San Francisco, CA, United States of America.
Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, United States of America.
PLoS One. 2019 Jul 18;14(7):e0220026. doi: 10.1371/journal.pone.0220026. eCollection 2019.
Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a genetically heterogeneous subtype of B-cell ALL characterized by chromosomal rearrangements and mutations that result in aberrant cytokine receptor and kinase signaling. In particular, chromosomal rearrangements resulting in the overexpression of cytokine receptor-like factor 2 (CRLF2) occur in 50% of Ph-like ALL cases. CRLF2 overexpression is associated with particularly poor clinical outcomes, though the molecular basis for this is currently unknown. Glucocorticoids (GCs) are integral to the treatment of ALL and GC resistance at diagnosis is an important negative prognostic factor. Given the importance of GCs in ALL therapy and the poor outcomes for patients with CRLF2 overexpression, we hypothesized that the aberrant signal transduction associated with CRLF2 overexpression might mediate intrinsic GC insensitivity. To test this hypothesis, we exposed Ph-like ALL cells from patient-derived xenografts to GCs and found that CRLF2 rearranged (CRLF2R) leukemias uniformly demonstrated reduced GC sensitivity in vitro. Furthermore, targeted inhibition of signal transduction with the MEK inhibitor trametinib and the Akt inhibitor MK2206, but not the JAK inhibitor ruxolitinib, was sufficient to augment GC sensitivity. These data suggest that suboptimal GC responses may in part underlie the poor clinical outcomes for patients with CRLF2 overexpression and provide rationale for combination therapy involving GCs and signal transduction inhibitors as a means of enhancing GC efficacy.
费城染色体样（Ph-样）急性淋巴细胞白血病（ALL）是一种具有遗传异质性的 B 细胞 ALL 亚型，其特征是存在染色体重排和突变，导致细胞因子受体和激酶信号异常。特别是，导致细胞因子受体样因子 2（CRLF2）过表达的染色体重排发生在 50%的 Ph-样 ALL 病例中。CRLF2 过表达与特别差的临床结局相关，尽管目前尚不清楚其分子基础。糖皮质激素（GCs）是 ALL 治疗的重要组成部分，诊断时的 GC 耐药是一个重要的预后不良因素。鉴于 GCs 在 ALL 治疗中的重要性以及 CRLF2 过表达患者的不良预后，我们假设与 CRLF2 过表达相关的异常信号转导可能介导内在的 GC 不敏感性。为了验证这一假设，我们将源自患者异种移植的 Ph-样 ALL 细胞暴露于 GCs 下，发现 CRLF2 重排（CRLF2R）白血病在体外均表现出 GC 敏感性降低。此外，用 MEK 抑制剂 trametinib 和 Akt 抑制剂 MK2206 靶向抑制信号转导，而不是用 JAK 抑制剂 ruxolitinib，足以增强 GC 敏感性。这些数据表明，GC 反应不佳可能部分解释了 CRLF2 过表达患者临床结局较差的原因，并为 GC 和信号转导抑制剂联合治疗提供了依据，以增强 GC 疗效。
