a Department of Biomedical Sciences , Cornell University , Ithaca , NY , USA.
b Robert Frederick Smith School of Chemical and Biomolecular Engineering , Cornell University , Ithaca , NY , USA.
Leuk Lymphoma. 2019 Jul;60(7):1697-1708. doi: 10.1080/10428194.2018.1543880. Epub 2018 Dec 20.
In non-acute promyelotic leukemia (APL)- non myelocytic leukemia (AML), identification of a signaling signature would predict potentially actionable targets to enhance differentiation effects of all-trans-retinoic acid (RA) and make combination differentiation therapy realizable. Components of such a signaling machine/signalsome found to drive RA-induced differentiation discerned in a FAB M2 cell line/model (HL-60) were further characterized and then compared against AML patient expression profiles. FICZ, known to enhance RA-induced differentiation, was used to experimentally augment signaling for analysis. FRET revealed novel signalsome protein associations: CD38 with pS376SLP76 and caveolin-1 with CD38 and AhR. The signaling molecules driving differentiation in HL-60 cluster in non-APL AML samples, too. Pearson correlation coefficients for this molecular ensemble are nearer 1 in the FAB M2 subtype than in non-APL AML. SLP76 correlation to RXRα and p47phox were conserved in FAB M2 model and patient subtype but not in general non-APL AML. The signalsome ergo identifies potential actionable targets in AML.
在非急性早幼粒细胞白血病（APL）-非髓性白血病（AML）中，鉴定信号特征将预测潜在的可操作靶点，以增强全反式维甲酸（RA）的分化作用，并使联合分化治疗成为可能。在 FAB M2 细胞系/模型（HL-60）中发现的驱动 RA 诱导分化的信号机器/信号体的组成部分进一步得到了表征，然后与 AML 患者的表达谱进行了比较。已知 FICZ 增强 RA 诱导的分化，用于实验性增强信号以进行分析。FRET 揭示了新的信号体蛋白关联：CD38 与 pS376SLP76 和 caveolin-1 与 CD38 和 AhR。在 HL-60 中驱动分化的信号分子也在非 APL AML 样本中聚集。在 FAB M2 亚型中，这个分子组合的皮尔逊相关系数比非 APL AML 更接近 1。在 FAB M2 模型和患者亚型中，SLP76 与 RXRα 和 p47phox 的相关性得到了保留，但在一般非 APL AML 中没有。因此，信号体确定了 AML 中的潜在可操作靶点。
