Oehler Vivian G, Guthrie Katherine A, Cummings Carrie L, Sabo Kathleen, Wood Brent L, Gooley Ted, Yang Taimei, Epping Mirjam T, Shou Yaping, Pogosova-Agadjanyan Era, Ladne Paula, Stirewalt Derek L, Abkowitz Janis L, Radich Jerald P
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Blood. 2009 Oct 8;114(15):3299-308. doi: 10.1182/blood-2008-07-170282. Epub 2009 Jul 22.
The preferentially expressed antigen in melanoma (PRAME) is expressed in several hematologic malignancies, but either is not expressed or is expressed at only low levels in normal hematopoietic cells, making it a target for cancer therapy. PRAME is a tumor-associated antigen and has been described as a corepressor of retinoic acid signaling in solid tumor cells, but its function in hematopoietic cells is unknown. PRAME mRNA expression increased with chronic myeloid leukemia (CML) disease progression and its detection in late chronic-phase CML patients before tyrosine kinase inhibitor therapy was associated with poorer therapeutic responses and ABL tyrosine kinase domain point mutations. In leukemia cell lines, PRAME protein expression inhibited granulocytic differentiation only in cell lines that differentiate along this lineage after all-trans retinoic acid (ATRA) exposure. Forced PRAME expression in normal hematopoietic progenitors, however, inhibited myeloid differentiation both in the presence and absence of ATRA, and this phenotype was reversed when PRAME was silenced in primary CML progenitors. These observations suggest that PRAME inhibits myeloid differentiation in certain myeloid leukemias, and that its function in these cells is lineage and phenotype dependent. Lastly, these observations suggest that PRAME is a target for both prognostic and therapeutic applications.
黑色素瘤优先表达抗原（PRAME）在多种血液系统恶性肿瘤中表达，但在正常造血细胞中要么不表达，要么仅低水平表达，这使其成为癌症治疗的靶点。PRAME是一种肿瘤相关抗原，在实体瘤细胞中被描述为视黄酸信号的共抑制因子，但其在造血细胞中的功能尚不清楚。PRAME mRNA表达随慢性髓性白血病（CML）疾病进展而增加，在酪氨酸激酶抑制剂治疗前检测晚期慢性期CML患者中的PRAME与较差的治疗反应和ABL酪氨酸激酶结构域点突变相关。在白血病细胞系中，PRAME蛋白表达仅在全反式维甲酸（ATRA）暴露后沿该谱系分化的细胞系中抑制粒细胞分化。然而，在正常造血祖细胞中强制表达PRAME，无论有无ATRA均抑制髓系分化，当在原发性CML祖细胞中沉默PRAME时，该表型逆转。这些观察结果表明，PRAME在某些髓系白血病中抑制髓系分化，且其在这些细胞中的功能取决于谱系和表型。最后，这些观察结果表明PRAME是预后和治疗应用的靶点。
