造血生成调节的关键因子:转录因子 HS C EKLF TFs are primordial AML1 in regulating the GATA-1 SCLI c-My b switch of the Red cells LMO2 hematopoietic AI NF-E2 organ, the lineage AML1 commitment and the differentiation c-Myb C/EBP-a,e Platelets of HSCs and progenitor cells Granulocyte GATA-2 AML TF genes related to GATA-3 hematopoiesis are evolutionarily well Monocyte/ conserved from the T cell B Macrophage zebrafish to human KO animals for some of these TFs exhibit phenoty pes of hematological disorders
造血生成调节的关键因子: 转录因子 Platelets Red cells TFs are primordial in regulating the switch of the hematopoietic organ, the lineage commitment and the differentiation of HSCs and progenitor cells TF genes related to hematopoiesis are evolutionarily well conserved from the zebrafish to human KO animals for some of these TFs exhibit phenotypes of hematological disorders
Chromosomal translocations and gene mutations In leukemlas ALL AML 30% Random Random AML1-E70 t821) 12%6 MYC BCR-ABL 7935/TCRB 98-HOXA9 14q11/CROs t7:11) MYC /296 CBFB-MYH11 t8;14)t(28)t82) 1% FUS-ERG 20% MLL-AF9 t1621) R2A-PBX1 TEL-AML E2A-HLF RARa/Ev! L fusions t411).1:11),1:19) tt5;17t11:17 NPM-MLFT Pro-s cell 口Mols口 Myelomonocytic口 Monoblastic Most of the fusion genes involved in AL translocations are transcription factors (TFs: abnormalities in lineage commitment and differentiation Look AT Science. 278: 1059
Look AT. Science, 278: 1059 Chromosomal translocations and gene mutations in leukemias Most of the fusion genes involved in AL translocations are transcription factors (TFs): abnormalities in lineage commitment and differentiation
Nodal points in controlling hematopoiesis: tyrosine kinases EGFR PDGFR FGFR NGFR EPHR DDR LMR InsulinR VEGFR KLG/CCK HGFR AXL MUSK KO mice for hematopoiesis related PTKs often show deficiency in 器下学器 CCK4·TRKA 怒器能, Alx ROR& MSK rko blood formation ERBB4 FLKSFLR EP松 PTKs FGR FYN SRC, YESI BLK HCK LCK LYN Hemato poiesis JAK1 JAK2, JAK3 TYK2 ACK ACK1 ACK2 = Actin badain domain related PtKs are CSK (SHDXSHDE CSK. MATKCTK essential factors in FAK FAK PyK2 DNA bad I eal arthron ttng determining FES CI FER FES nn tanning domain growth and survival FRK“SHdH□ BRK. FRK, SRMS TEc回d BMX BTK IIK. TEC, TXK of hscs and See henlow 2 deman SYK( SH2)(SH2 SYK ZAPTO progenitor cells
Nodal points in controlling hematopoiesis: tyrosine kinases PTKs Hematopoiesis related PTKs are essential factors in determining growth and survival of HSCs and progenitor cells KO mice for hematopoiesis related PTKs often show deficiency in blood formation
Chromosomal translocations and gene mutations in leukemias Chromosome 22 Chromosome 9 1-bcr BCR BCR-ABL, a M-bcr a model of activation ABL protein e19 tyrosine bcr p kinase(PTK) in leukemi genesis growth and survival ■/Ⅲ■→ b2a2 advantages 心p210BcR-ABL ■II ∥ ■/I/Ⅲ/■→2→p23)RAB
Chromosomal translocations and gene mutations in leukemias BCR-ABL, a model of activation of protein tyrosine kinase (PTK) in leukemogenesis: growth and survival advantages
白血病基因组解剖学计划(L-GAP) 必要性:约50%的白血病患者无染色体异常,即使有特异的 基因异常也不足以产生典型的白血病(如AMLM2b的AML1 ETO;CML的BCR-ABL);大多数白血病患者无病生存期远不 理想 ·大规模系统性候选基因(造血系统转录因子和胞浆信号分子 尤其是酪氨酸激酶)的基因突变检测及蛋白质功能研究。 ·基于药物靶点的高通量筛选库(传统中药天然药物库,组合 化学合成物库)和基于信号传导途径知识的药物设计/组合
白血病基因组解剖学计划 (L-GAP) 必要性:约50％的白血病患者无染色体异常，即使有特异的 基因异常也不足以产生典型的白血病（如AML-M2b的AML1- ETO; CML的BCR-ABL）；大多数白血病患者无病生存期远不 理想。 大规模系统性候选基因（造血系统转录因子和胞浆信号分子 尤其是酪氨酸激酶）的基因突变检测及蛋白质功能研究。 基于药物靶点的高通量筛选库（传统中药天然药物库，组合 化学合成物库）和基于信号传导途径知识的药物设计/组合