Transcriptome of chronic myeloid leukemia blood in early disease based on RNA-seq method
ABSTRACT: In order to support our research of chronic myeloid leukemia in human genome, we conducted massively parallel pyrosequencing of mRNAs (RNA-seq) using chronic myeloid leukemia blood in early disease. We obtained a total of 17.74 million read pairs from blood in early disease.The RNA-seq data derived from the sample illustrated the expreesion genes in chronic myeloid leukemia blood in early disease of human. 1 sample examined: blood in early disease.
Project description:In order to detect the transcriptomic differences during chemotherapy treatment of de novo AML, we adopted massively parallel pyrosequencing of mRNAs (RNA-seq) using blood tissues of an patient with AML (FAB subtype M2) in tumor stage and remission stage. We obtained a total of 34.6 and 30.8 million paired reads from the two samples. The RNA-seq data derived from the sample illustrated the differentially expression genes between the two stages. Blood samples of an AML-M2 patient in two stages examined: primary tumor and chemotherapy induced remission.
Project description:A single hematopoietic stem cell can give rise to all blood cells with remarkable fidelity. Here, we define the chromatin accessibility and transcriptional landscape controlling this process in thirteen primary cell types that traverse the hematopoietic hierarchy. Exploiting the finding that enhancer landscapes better reflect cell identity than mRNA levels, we enable "enhancer cytometry" for accurate enumeration of pure cell types from complex populations. We further reveal the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia, chromatin accessibility reveals distinctive regulatory evolution in pre-leukemic HSCs (pHSCs), leukemia stem cells, and leukemic blasts. These leukemic cells demonstrate unique lineage infidelity, confirmed by single cell regulomes. We further show that pHSCs have a competitive advantage that is conferred by reduced chromatin accessibility at HOXA9 targets and is associated with adverse patient outcomes. Thus, regulome dynamics can provide diverse insights into human hematopoietic development and disease. Single-cell ATAC-seq of LMPPs, Monocytes, LSCs and Luekemic blast cells.
Project description:B cell chronic lymphocytic leukemia - A model with immune response
Seema Nanda 1, , Lisette dePillis 2, and Ami Radunskaya 3,
Tata Institute of Fundamental Research, Centre for Applicable Mathematics, Bangalore 560065, India
Department of Mathematics, Harvey Mudd College, Claremont, CA 91711
Department of Mathematics, Pomona College, Claremont, CA, 91711, United States
B cell chronic lymphocytic leukemia (B-CLL) is known to have substantial clinical heterogeneity. There is no cure, but treatments allow for disease management. However, the wide range of clinical courses experienced by B-CLL patients makes prognosis and hence treatment a significant challenge. In an attempt to study disease progression across different patients via a unified yet flexible approach, we present a mathematical model of B-CLL with immune response, that can capture both rapid and slow disease progression. This model includes four different cell populations in the peripheral blood of humans: B-CLL cells, NK cells, cytotoxic T cells and helper T cells. We analyze existing data in the medical literature, determine ranges of values for parameters of the model, and compare our model outcomes to clinical patient data. The goal of this work is to provide a tool that may shed light on factors affecting the course of disease progression in patients. This modeling tool can serve as a foundation upon which future treatments can be based.
Keywords: NK cell, chronic lymphocytic leukemia, mathematical model, T cell., B-CLL.
Project description:RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia-associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML). Overall design: Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc.
Project description:RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia-associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML). Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc.
Project description:Genomic studies in chronic myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and MPN/MDS, have identified common mutations in genes encoding signaling, epigenetic, transcription and splicing factors. Analysis of 18 of these genes in a cohort of 224 chronic myelomonocytic leukemias (CMML), which is the most frequent MPN/MDS, identified at least one mutated gene in 95% of the patients, with some of the mutations affecting the disease phenotype. The number of mutated genes negatively affected progression-free and overall survival in multivariate analysis. Analysis of sorted progenitors indicated an early amplification of the CMML clone at the CD34+/CD38- stage of hematopoiesis, together with a premature granulomonocytic differentiation skewing. We interrogated the clone architecture by mutation-specific discrimination analysis of single-cell-derived colonies. The genetic classification of individual colonies allowed a designation of sub-clones and the assembly of putative evolutionary trees, indicating a linear acquisition of the studied mutations. Analysis of matched pre- and post-treatment samples demonstrated clonal persistence with limited and selective elimination of sub-clones. The disease was characterized by an amplification of multipotent and common myeloid progenitors in the CD34+ compartment, both fractions showing increased granulomonocytic differentiation at the expense of erythroid progenitors, contrasting with normal granulomonocytic progenitors. Altogether, early amplification of the leukemic clone and increased granulomonocytic differentiation of early progenitors may account for the specificity of CMML among myeloid neoplasms. This experiment correspond to the analysis of gene expression profiles in total CD34+ cells from the peripheral blood of 15 patients (Chronic Myelomonocytic Leukemia) and 4 healthy controls.
Project description:An in-depth analysis of miRNomes in 3 human myeloid leukemia cell lines was carried out to comprehensively identify miRNAs that distinguish acute and chronic myeloid leukemias and relate to myeloid cell differentiation. Characterization the miRNomes in 3 myeloid leukemia cell lines.
Project description:Hematopoietic stem cells (HSCs) and lymphoid-primed multi-potential progenitors (LMPPs) are able to initiate both lymphoid and myeloid differentiation. We show here that the transcriptional repressor Gfi1 (growth factor independence 1) implements a specific gene expression program in HSCs and LMPPs that is critical for their survival and lymphoid differentiation potential. We present evidence that Gfi1 is required to maintain expression of genes involved in lymphoid development such as Flt-3, IL7R, Ebf1, Rag1, CCR9 and Notch1 and controls myeloid lineage commitment by regulating expression of genes such as Hoxa9 or M-CSFR. Gfi1 also inhibits apoptosis in HSCs by repressing pro-apoptotic genes such as Bax or Bak. As a consequence, Gfi1-/- mice show defects in self renewal, survival and both myeloid and lymphoid development of HSCs and LMPPs. Co-expression of a Bcl-2 transgene can partially restore the function of HSCs in Gfi1-/- mice, but not the defects in early lymphoid development. Of interest, Gfi1-/- x Bcl-2 transgenic mice show an accelerated expansion of myeloid cells and succumb to a fatal myeloproliferative disease resembling chronic myelomonocytic leukemia (CMML). Our data show that Gfi1 protects HSCs against apoptosis, ensures the proper development of LMPPs and plays a role in the development of myeloid leukemia. We used microarrays to detail the global gene expression changes following knockout of Gfi1 in mouse LSK cells We compared LSK cells isolated from Gfi1 knockout mice with wildtype cells to determine global gene expression changes by microarray analysis
Project description:Identification of differentially expressed genes in the blood of chronic phase patients with chronic myeloid leukemia (CML) harboring different bcr-abl transcript variants. All leukemic samples were collected prior to therapy at the time point of the initial diagnosis of CML.