肿瘤学细胞分化课件.pptVIP

1990: Multiple groups identify RARa as t(15; 17) breakpoint Acute Promyelocytic Leukemia How do you test if a fusion protein is oncogenic? How does PML-RARa induces APL?How does ATRA induce remission? Does loss of one copy of PU.1 contribute to PML-RARa driven APL? YES: PU.1+/- mice expressing PML-RARa have a high penetrance of APL PU.1 mutations in 9 of 126 AML pts * Cell Differentiation Cancer 细胞分化（differentiation）是指同源细胞逐渐发育成具备稳定形态结构、生理功能和生化特征的另一类型细胞的过程。 细胞分化过程是由一系列基因产物（regulatory proteins）调控的。 i.e., 每个基因的表达都必须： 在正确的细胞中； 在正确的时间； 对正确的信号产生正确的反应； 产生正确的表达水平。 例子：眼形成的关键调控蛋白Ey（果蝇） ey 基因 早期细胞（发育成腿） 腿中眼细胞分化 眼形成 Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors Cell 2007,131,861-872 （Oct3/4, Sox2, Klf4, c-Myc ） Leukemia Acute Chronic Lymphoid Myeloid Lymphoid Myeloid (CLL) (CML) (ALL) AML M0 M1 M2 M3 M4 M5 M6 M7 FAB: /. ../wcd/myeloid1.cfm M2 t(8;21) AML1-ETO M1 t(9;22) M5 t(9;11) M3 t(15;17) PML-RARα acute promyelocytic leukemia “Acute myelogenous leukemias (AMLs) are genetically heterogeneous and characterized by chromosomal rearrangements that produce fusion proteins with aberrant transcriptional regulatory activities.” Myriam Alcalay et. al., 2003 FAB, Translocation and Fusion Proteins M3 t(15;17) PML-RARα acute promyelocytic leukemia “Acute promyelocytic leukemia (AML M3) is now the most frequently curable acute leukaemia in adults if promptly diagnosed and adequately treated.” Parmar S, Tallman MS. , 2003 Differentiation Therapy Differentiation therapies are broadly defined as those that induce malignant reversion (i.e. the malignant phenotype becomes benign). Clinically, these therapies have been most successful for acute promyelocytic leukemia (APL), with the use of all-trans retinoic acid (ATRA). This treatment has changed a cancer with a previously dismal outcome into one of the most treatable forms of leukemia. The exact mechanism