Randolph T R
Department of Clinical Laboratory Science, School of Allied Health Professions, Saint Louis University Health Sciences Center, MO 63104-1111, USA.
Clin Lab Sci. 2000 Spring;13(2):106-16.
To identify the chromosomal translocation common in M3 and discuss its diagnostic use to: Compare acute leukemia with chronic leukemia and other forms of cancer. Describe the molecular defect including the fusion gene and fusion protein produced from the translocation. Discuss the proposed mechanism of leukemogenesis in M3. Discuss the proposed mechanism of differentiation induction stimulated by ATRA therapy. Present the future direction of this and other forms of therapy.
Current literature.
Acute promyelocytic leukemia (AML-M3) is a form of acute leukemia that presents with a less dramatic leukocytosis, anemia, and thrombocytopenia than other acute leukemias. However, AML-M3 has a lower first remission rate and a higher morbidity and mortality rate than most of the other acute leukemias when treated with conventional chemotherapy. AML-M3 frequently stimulates a serious concomitant coagulation disorder, disseminated intravascular coagulation, which is a major contributor to the high mortality rate. This and other devastating sequela of M3 have prompted clinicians and investigators to develop methods of improving diagnosis and therapy. In 1977 the method of diagnosis confirmation was improved by the identification of a consistent chromosomal translocation involving the long arms of chromosomes 15 and 17. Identification of the specific molecular lesion that produced the t(15;17) translocation occurred in 1990 and was shown to involve the retinoic acid receptor alpha gene (RAR alpha). Because the RAR alpha gene is mutated in all AML-M3 patients studied so far and because it is often the only mutation identified, several proposed mechanisms of leukemogenesis have evolved. From these discoveries a novel approach to cancer treatment focusing on differentiation therapy instead of traditional chemotherapy emerged. All-trans retinoic acid (ATRA) has been shown to stimulate differentiation of promyelocytes from the malignant clone and has become an important element in the treatment of patients with AML-M3.
Since the discovery of the t(15;17) translocation, the identification of the fusion gene containing the retinoic acid receptor alpha, and the success of ATRA as a form of differentiation therapy, the diagnosis and treatment of AML-M3 has dramatically improved. In addition, AML-M3 has become a model system used to study the mechanisms that produce uncontrolled growth and lack of differentiation in leukemic cells (leukemogenesis) and the mechanisms of therapeutic reversal of this block in differentiation (differentiation therapy).
确定M3中常见的染色体易位，并讨论其诊断用途，以：比较急性白血病与慢性白血病及其他癌症形式。描述分子缺陷，包括由该易位产生的融合基因和融合蛋白。讨论M3白血病发生的拟议机制。讨论全反式维甲酸（ATRA）治疗所激发的分化诱导的拟议机制。介绍这种及其他治疗形式的未来方向。
当前文献。
急性早幼粒细胞白血病（AML-M3）是急性白血病的一种形式，与其他急性白血病相比，其白细胞增多、贫血和血小板减少的症状不那么明显。然而，与大多数其他急性白血病相比，AML-M3采用传统化疗时首次缓解率较低，发病率和死亡率较高。AML-M3经常引发严重的伴随凝血障碍，即弥散性血管内凝血，这是高死亡率的主要原因。M3的这种及其他破坏性后果促使临床医生和研究人员开发改进诊断和治疗的方法。1977年，通过识别涉及15号和17号染色体长臂的一致染色体易位，诊断确认方法得到改进。1990年确定了产生t(15;17)易位的特定分子病变，显示其涉及维甲酸受体α基因（RARα）。由于RARα基因在迄今研究的所有AML-M3患者中均发生突变，且往往是唯一确定的突变，因此出现了几种白血病发生的拟议机制。基于这些发现，出现了一种以分化治疗而非传统化疗为重点的新型癌症治疗方法。全反式维甲酸（ATRA）已被证明可刺激恶性克隆中的早幼粒细胞分化，并已成为AML-M3患者治疗中的重要元素。
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