Andreeff M, Jiang S, Zhang X, Konopleva M, Estrov Z, Snell V E, Xie Z, Okcu M F, Sanchez-Williams G, Dong J, Estey E H, Champlin R C, Kornblau S M, Reed J C, Zhao S
Department of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Leukemia. 1999 Nov;13(11):1881-92. doi: 10.1038/sj.leu.2401573.
The expression of Bcl-2 family members was examined in normal and leukemic hematopoietic cells. Immature hematopoietic progenitor cells (CD34+/33-/13-) did not express Bcl-2 but Bcl-XL, the majority of CD34 cells expressed Bcl-2, Bcl-XL and BAD, and normal promyelocytes (CD34-/33+) lacked expression of both Bcl-2 and Bcl-XL, while leukemic CD34+progenitors and promyelocytes expressed these anti-apoptotic proteins. In AML, Bcl-2 expression was higher on CD34+ than on all AML cells, however, expression of Bcl-2 or Bcl-XL did not predict achievement of complete remission. Surprisingly, low Bcl-2 content was associated with poor survival in a group of patients with poor prognosis cytogenetics. The anti-apoptotic BAD protein was found to be expressed in AML, but was phosphorylated in 41/42 samples. Phosphorylation was found at both sites, Ser 112 and Ser 136. During induction chemotherapy, Bcl-2 levels of CD34 cells increased significantly. In the context of evidence for small numbers of leukemic CD34+ cells expressing very high levels of Bcl-2 prior to therapy, this finding is interpreted as a survival advantage of Bcl-2 overexpressing progenitors and rapid elimination of cells with low Bcl-2. Bcl-2 and Bcl-XL were both expressed in minimal residual disease cells. Downregulation of Bcl-2 mRNA and protein was observed by ATRA and the combination of Ara-C, followed by ATRA, resulted in markedly increased cytotoxicity in HL-60 cells, as compared to Ara-C alone or ATRA followed by Ara-C. Implications of these findings for the development of new therapeutic strategies for AML are discussed.
在正常和白血病造血细胞中检测了Bcl-2家族成员的表达。未成熟造血祖细胞（CD34+/33-/13-）不表达Bcl-2但表达Bcl-XL，大多数CD34细胞表达Bcl-2、Bcl-XL和BAD，正常早幼粒细胞（CD34-/33+）不表达Bcl-2和Bcl-XL，而白血病CD34+祖细胞和早幼粒细胞表达这些抗凋亡蛋白。在急性髓系白血病（AML）中，CD34+细胞上Bcl-2的表达高于所有AML细胞，但Bcl-2或Bcl-XL的表达不能预测完全缓解的实现。令人惊讶的是，在一组预后不良细胞遗传学的患者中，低Bcl-2含量与不良生存相关。发现抗凋亡BAD蛋白在AML中表达，但在41/42个样本中被磷酸化。在丝氨酸112和丝氨酸136位点均发现磷酸化。在诱导化疗期间，CD34细胞的Bcl-2水平显著增加。鉴于有证据表明少数白血病CD34+细胞在治疗前表达非常高水平的Bcl-2，这一发现被解释为Bcl-2过表达祖细胞的生存优势以及低Bcl-2细胞的快速清除。Bcl-2和Bcl-XL均在微小残留病细胞中表达。全反式维甲酸（ATRA）可观察到Bcl-2 mRNA和蛋白的下调，与单独使用阿糖胞苷（Ara-C）或先使用ATRA后使用Ara-C相比，Ara-C联合ATRA后再使用ATRA可导致HL-60细胞的细胞毒性显著增加。讨论了这些发现对AML新治疗策略开发的意义。
