Collaborative Pathways that Lead to Leukemia

导致白血病的协同途径

• 批准号: 9556417
• 负责人: Peter Aplan
• 金额: $ 61.77万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9556417
• 关键词: Acute leukemia; Animal Model; Apoptosis; Candidate Disease Gene; Cells; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Epigenetic Process; Gene Expression Profile; Generations; Genes; Genetic; Genetic Crosses; Genetically Engineered Mouse; Hematopoietic; Hematopoietic stem cells; Human; Immunophenotyping; Impairment; Insertional Mutagenesis; Lead; Lymphoma; Manuscripts; Mouse Strains; Mus; Mutate; Mutation; Myeloid Leukemia; NUP98 gene; Pathway interactions; Preparation; Proto-Oncogene Protein c-kit; Publishing; Sampling; Small Interfering RNA; Stem cells; T-Lymphocyte; TOP1 gene; Transgenes; Transgenic Mice; Transplantation; clinically relevant; deep sequencing; exome; exome sequencing; human disease; in vivo; leukemia; offspring; progenitor; retroviral transduction; self-renewal; whole genome

We previously identified mutations of candidate genes including Flt3, Nras, Kras, Ptpn11, and Cbl. More recently, in collaboration with Dr. Paul Meltzer, we have used multiplex PCR and deep sequencing to identify mutations in 24 candidate genes in a set of 152 mouse leukemias and identified spontaneous, acquired mutations in Nras, Kras, Tp53, Notch1, Flt3, Ptpn11, Cbl, and Idh1; a manuscript describing these findings is in preparation. Again, in collaboration with Dr. Meltzer, we analyzed whole-exome deep sequence of the leukemias that develop in NUP98-PHF23 (NP23) mice and the PTCL that developed in Lin28b mice. Unexpectedly, we identified frequent mutations in progenitor B1 cell ALL in the Bcor and Jak1/2 genes. A manuscript describing these findings is currently in press. Furthermore, we have used CRISPR to introduce Bcor mutations in primary WT and NP23 BM cells; these cells have been transplanted into recipient mice to determine if we can verify collaboration between NP23 and Bcor in vivo. Additional in vivo genetic crosses, performed in collaboration with Dr. Donald Small and Dr. Trang Hoang have demonstrated that the NHD13 transgene can collaborate with a Flt3 ITD to induce a myeloid leukemia, and there is an in vivo interaction between SCL and c-Kit that is important for early hematopoietic differentiation. A manuscript describing the Flt3 and NHD13 interaction, as well as its potential clinical relevance, has recently been published. As mentioned above, spontaneous mutations of IDH2 were identified in NHD13 leukemias. These mutations occur at R140Q; homologous residues are mutated in human leukemia. We crossed IDH2 R140Q transgenic mice with NHD13 mice; the offspring develop a form of early T cell precursor (ETP) leukemia that resembles the human disease in terms of clinical presentation, immunophenotype, gene expression profile, and collaborative mutations. A manuscript describing these findings is in preparation.

我们先前鉴定了包括FLT3，NRA，KRAS，PTPN11和CBL在内的候选基因的突变。最近，我们与Paul Meltzer博士合作，我们使用了多重PCR和深层测序来鉴定一组152个小鼠白血病中24个候选基因的突变，并在NRAS，KRAS，TP53，NOTCH1，FLT3，FLT3，FLT3，FLT3，FLT3，FLT3，FLT3，FLT3，FLT3，FLT3，NOTCH1，FLT3，FLT3，FLT3，FLT3，notch1，notch1，noctand offeration selectane sejection基因中识别出自发的突变。 PTPN11，CBL和IDH1;描述这些发现的手稿正在准备。同样，在与Meltzer博士的合作中，我们分析了NUP98-PHF23（NP23）小鼠中发育的白血病的全外观深层，以及在LIN28B小鼠中开发的PTCL。出乎意料的是，我们确定了BCOR和JAK1/2基因的祖细胞B1细胞中的频繁突变。描述这些发现的手稿目前正在印刷中。此外，我们已经使用CRISPR在原代WT和NP23 BM细胞中引入BCOR突变。这些细胞已被移植到受体小鼠中，以确定我们是否可以验证NP23和BCOR之间的协作。与Donald Small博士和Trang Hoang博士合作进行的其他体内遗传十字架已经证明，NHD13 Transgene可以与FLT3 ITD合作诱导髓样白血病，并且SCL和C-KIT之间存在体内互动这对于早期造血分化很重要。最近发表了描述FLT3和NHD13相互作用及其潜在临床相关性的手稿。如上所述，在NHD13白血病中发现了IDH2的自发突变。这些突变发生在R140Q；同源残留在人白血病中突变。我们用NHD13小鼠越过IDH2 R140Q转基因小鼠；后代发展了早期T细胞前体（ETP）白血病的一种形式，该形式在临床表现，免疫表型，基因表达谱和协作突变方面类似于人类疾病。描述这些发现的手稿正在准备。