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Gene expression profiling of CD34(+) cells from patients with myeloproliferative neoplasms.

ABSTRACT: Myeloproliferative neoplasms (MPN) are clonal disorders characterized by the increased proliferation of hematopoietic stem cell precursors and mature blood cells. Mutations of Janus kinase 2 (JAK2), Calreticulin (CALR) and MPL (myeloproliferative leukemia virus) are key driver mutations in MPN. However, the molecular profile of triple negative MPN has been a subject of ambiguity over the past few years. Mutations of, methylcytosine dioxygenase TET2, polycomb group protein ASXL1 and histone-lysine N-methyltransferase EZH2 genes have accounted for certain subsets of triple negative MPNs but the driving cause for majority of cases is still unexplored. The present study performed a microarray-based transcriptomic profile analysis of bone marrow-derived CD34(+) cells from seven MPN samples. A total of 21,448 gene signatures were obtained, which were further filtered into 472 upregulated and 202 downregulated genes. Gene ontology and protein-protein interaction (PPI) network analysis highlighted an upregulation of genes involved in cell cycle and chromatin modification in JAK2V617F negative vs. positive MPN samples. Out of the upregulated genes, seven were associated with the hematopoietic stem cell signature, while forty-seven were associated with the embryonic stem cell signature. The majority of the genes identified were under the control of NANOG and E2F4 transcription factors. The PPI network indicated a strong interaction between chromatin modifiers and cell cycle genes, such as histone-lysine N-methyltransferase SUV39H1, SWI/SNF complex subunit SMARCC2, SMARCE2, chromatin remodeling complex subunit SS18, tubulin ? (TUBB) and cyclin dependent kinase CDK1. Among the upregulated epigenetic markers, there was a ~10-fold increase in MYB expression in JAK2V617F negative samples. A significant increase in total CD34 counts in JAK2V617F negative vs. positive samples (P<0.05) was also observed. Overall, the present data showed a distinct pattern of expression in JAK2V617F negative vs. positive samples with upregulated genes involved in epigenetic modification.

SUBMITTER: Sharma M

PROVIDER: S-EPMC7816297 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Gene expression profiling of CD34(+) cells from patients with myeloproliferative neoplasms.

Sharma Mugdha M Bhavani Chandra C Suresh Srinag Bangalore SB Paul John J Yadav Lokendra L Ross Cecil C Srivastava Sweta S

Oncology letters 20210112 3

Myeloproliferative neoplasms (MPN) are clonal disorders characterized by the increased proliferation of hematopoietic stem cell precursors and mature blood cells. Mutations of Janus kinase 2 (JAK2), Calreticulin (CALR) and MPL (myeloproliferative leukemia virus) are key driver mutations in MPN. However, the molecular profile of triple negative MPN has been a subject of ambiguity over the past few years. Mutations of, methylcytosine dioxygenase TET2, polycomb group pro ...[more]

PMID: 33574943

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Project description:Myeloproliferative neoplasms (MPNs) are clinically characterized by the chronic overproduction of differentiated peripheral blood cells and the gradual expansion of malignant intramedullary/extramedullary hematopoiesis. In MPNs mutations in JAK2 MPL or CALR are detected mutually exclusive in more than 90% of cases [1,2]. Mutations in them lead to the abnormal activation of JAK/STAT signaling and the autonomous growth of differentiated cells therefore they are considered as "driver" gene mutations. In addition to the above driver gene mutations mutations in epigenetic regulators such as TET2 DNMT3A ASXL1 EZH2 or IDH1/2 are detected in about 5%-30% of cases respectively [3]. Mutations in TET2 DNMT3A EZH2 or IDH1/2 commonly confer the increased self-renewal capacity on normal hematopoietic stem cells (HSCs) but they do not lead to the autonomous growth of differentiated cells and only exhibit subtle clinical phenotypes [4,6-8,5]. It was unclear how mutations in such epigenetic regulators influenced abnormal HSCs with driver gene mutations how they influenced the disease phenotype or whether a single driver gene mutation was sufficient for the initiation of human MPNs. Therefore we focused on JAK2V617F and loss of TET2-the former as a representative of driver gene mutations and the latter as a representative of mutations in epigenetic regulators-and examined the influence of single or double mutations on HSCs (Lineage(-)Sca-1(+)c-Kit(+) cells (LSKs)) by functional analyses and microarray whole-genome expression analyses [9]. Gene expression profiling showed that the HSC fingerprint genes [10] was statistically equally enriched in TET2-knockdown-LSKs but negatively enriched in JAK2V617F-LSKs compared to that in wild-type-LSKs. Double-mutant-LSKs showed the same tendency as JAK2V617F-LSKs in terms of their HSC fingerprint genes but the expression of individual genes differed between the two groups. Among 245 HSC fingerprint genes 100 were more highly expressed in double-mutant-LSKs than in JAK2V617F-LSKs. These altered gene expressions might partly explain the mechanisms of initiation and progression of MPNs which was observed in the functional analyses [9]. Here we describe gene expression profiles deposited at the Gene Expression Omnibus (GEO) under the accession number GSE62302 including experimental methods and quality control analyses.

Project description:Myeloproliferative neoplasms (MPN) are clonal hematopoietic diseases that include essential thrombocytosis (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) as well as BCR-ABL+ chronic myelogenous leukemia (CML). In the past several years, studies with cDNA microarrays have defined patterns of gene expression corresponding to specific molecular abnormalities, oncologic phenotypes, and clinical outcomes in hematologic malignancies. This study was aimed at the description of a gene expression signature in MPN which would eventually present a new pathogenetic approaching and also diagnostic as well as prognostic information. Using cDNA microarray analysis, involving 25,100 unique genes, we studied the gene expression profile of the pluripotent hematopoietic CD34+ stem cells and mature granulocytes obtained from peripheral blood of ET, PV, PMF and CML patients compared with healthy individuals. The average number of CD34+ cells (cells/µl) in peripheral blood was approximately 6 in PV and ET, 111 in PMF and 2880 in CML as measured by flow cytometry. A somatic point mutation JAK2V617F was detected in 93% of PV, 73% of PMF and 55% of ET patients within genetically homogenous population. The homozigosity for JAK2V617F mutation was the highest in PV (60%), less prominent in PMF (42%) and low in ET (11%) patients. The JAK2V617F mutation negative patients were also negative for exon 12 mutations. Approximately 420, 680 and 1130 genes had unique expression among CD34+ cells of ET, PV and PMF patients, respectively. In addition comparing to healthy controls, ET, PV, PMF and CML patients showed difference in 840, 1180, 1160 and 2050 expressed genes, respectively. Furthermore, we studied EPO and JAK-STAT signaling pathways related genes expression in MPN. The FOS, RAF1 and JAK2 gene expression, related to EPO signaling pathway, was elevated in ET, PV, PMF and reduced in CML comparing to healthy controls. Related to these genes, the JAK2V617F mutation homozygous and heterozygous patients generally displayed more significant differences comparing to patients with no mutation. STAT5 gene expression was decreased in all MPN patients. CSF3R, STAT1 and STAT3 gene expression, related to JAK-STAT signaling pathway, was elevated in ET, PV, PMF and reduced in CML comparing to healthy controls. CREBBP gene expression was reduced in CD34+ cells of ET, PV and PMF patients, but during maturation it enhanced expression in granulocytes. In conclusion, molecular profiling of CD34+ cells and granulocytes revealed a certain number of genes with changed expression that, beyond their recognized function in disease pathogenesis, can be related to patients’ clinical characteristics and may have an imminent prognostic relevance.

Dataset Information

Gene expression profiling of CD34(+) cells from patients with myeloproliferative neoplasms.

Publications

Gene expression profiling of CD34(+) cells from patients with myeloproliferative neoplasms.

Similar Datasets

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