scholarly journals A Transcriptomic Continuum of Differentiation Arrest in Acute Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2511-2511
Author(s):  
Jonathan Bond ◽  
Aleksandra Krzywon ◽  
Ludovic Lhermitte ◽  
Christophe Roumier ◽  
Anne Roggy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Selection ◽  
Early Stage ◽  
Myeloid Cell ◽  
Clustering Methods ◽  
Humanized Mouse Model ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Lymphoid Progenitors

Introduction: Traditional classification of acute lymphoblastic and myeloid leukemias (ALLs and AMLs) remains heavily based on phenotypic resemblance to normal hematopoietic precursors of the respective lineages. This framework can provide diagnostic challenges for immunophenotypically heterogeneous immature leukemias, which often have poor responses to treatment. This system also takes little account of modern concepts of hematopoietic identity that are mainly based on transcriptional signature identification and functional assays. Recent advances in genome-wide analytical methods developed to reconstruct landscapes of normal differentiation now provide an opportunity to re-evaluate traditional binary approaches to myeloid and lymphoid lineage assignment in leukemia. Methods: We used novel computational tools, including the recently described Iterative Clustering and Guide Gene Selection (ICGS) method to perform transcriptional analyses of a series of 125 T-ALLs and AMLs, which comprised a high proportion of phenotypically immature cases (53.1% and 40.8% respectively). The leukemias were additionally characterized by targeted next generation sequencing (NGS). ICGS was also used to analyze independent adult and pediatric T-ALL cohorts. Results: There was significant overlap in gene expression between leukemias of different diagnostic categories. In contrast to traditional clustering methods, ICGS analysis permitted unbiased classification of acute leukemias along a continuum of hematopoietic differentiation, according to the expression of a limited number of lineage-discriminating guide genes that defined hematopoietic cell expression modules. While AMLs and T-ALLs at either end of the differentiation spectrum showed specific enrichment for transcriptional signatures of the corresponding lineage precursors, leukemias that were arrested at the myeloid/ T-lymphoid interface either showed no clear evidence of mature T-lymphoid or mature myeloid identity, or had incomplete Hematopoietic Stem and Progenitor Cell (HSPC) and mature myeloid cell profiles. NGS analysis revealed that the spectrum of differentiation arrest defined by ICGS is only partially paralleled by underlying mutational genotype. Notably, interface leukemias originally diagnosed as T-ALL were significantly more likely to have PTEN mutations than the rest of the T-ALL cohort (60% v 6.7%, p=0.0151), while RUNX1-mutated AMLs were restricted to interface clusters. We found that interface leukemias shared gene expression programs with a series of multi- or oligopotent hematopoietic progenitor populations, including the most immature CD34+CD1a-CD7- subset of early thymic precursors (ETPs). Within interface leukemias, enrichment for lymphoid progenitor population signatures including multi-lymphoid progenitors (MLPs), lymphoid-mono-dendritic progenitors (LMDPs), T-oriented CD127- and B-oriented CD127+ early lymphoid progenitors (ELPs) from an umbilical cord blood humanized mouse model and early B-cell progenitors, was more likely in cases that were originally diagnosed as AML, rather than T-ALL. In addition, transcriptional resemblance to both B/myeloid and T/myeloid mixed phenotype acute leukemias (MPALs) was primarily driven by AMLs within these interface clusters, suggesting that these cases demonstrate significant lymphoid transcriptional orientation. Conclusion: Our results suggest that traditional binary approaches to leukemia categorization are reductive, and that leukemias arrested at the T-lymphoid/ myeloid interface exhibit significant transcriptional heterogeneity. These data also provide evidence that a subset of leukemias originally diagnosed as AML may be more likely to arise from lymphoid-oriented progenitors and/or be arrested at an early stage of lymphoid orientation than is currently recognized. We believe that better identification of interface acute leukemias will allow improved evaluation of appropriate therapeutic options for these cases. Disclosures Boissel: NOVARTIS: Consultancy. Laurenti:GSK: Research Funding.

Ezh2 and Runx1 Mutations Targeted to Early Lymphoid Progenitors Collaborate to Promote Early Thymic Progenitor Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 846-846
Author(s):  
Christopher Booth ◽  
Nikolas Barkas ◽  
Wen Hao Neo ◽  
Elizabeth Soilleux ◽  
Hanane Boukarabila ◽  
...  
Keyword(s):  
Gene Expression ◽  
Conflicts Of Interest ◽  
Myeloid Cell ◽  
High Sensitivity ◽  
Response To Therapy ◽  
Ras Signaling ◽  
Specific Cell ◽  
Cell Of Origin ◽  
Hematopoietic Stem ◽  
Lymphoid Progenitors

Abstract Understanding the specific cell populations responsible for propagation of leukemia is an important step for development of effective targeted therapies. Recently, the lymphoid-primed multipotent progenitor (LMPP) has been proposed to be a key propagating population in acute myeloid leukemia (AML; PMID 21251617). We have also shown that LMPPs share many functional and gene expression properties with early thymic progenitors (ETPs; PMID 22344248). This finding is of particular interest as ETP leukemias have recently been described: a distinct and poor prognostic disease entity with a transcriptional profile reminiscent of murine ETPs, showing co-expression of hematopoietic stem cell (HSC) and myeloid markers (PMID 19147408). Together, this raises the question whether ETPs can act as a leukemia-initiating/propagating cell population; however, relevant disease models to test this hypothesis are currently lacking. Analysis of the genetic landscape of ETP leukemias has revealed frequent coexistence of inactivating mutations of EZH2 and RUNX1 (PMID 22237106). We therefore generated mice with deletions of Ezh2 and Runx1 specifically targeted to early lymphoid progenitors using Rag1Cre (Ezh2fl/flRunx1fl/flRag1Cre+; DKO mice). As anticipated, HSCs lacked significant recombination in DKO mice whereas close to 100% of purified ETPs (Lin- CD4- CD8- CD44+ CD25- Kit+ Flt3+) showed deletion of Ezh2 and Runx1. Strikingly, despite a 16-fold reduction in thymus cellularity caused by a block in thymocyte maturation at the DN2-DN3 transition, absolute numbers of ETPs within the thymus of DKO mice were markedly expanded (12-fold; p<0.0001). In contrast, Ezh2 or Runx1 deletion alone had no impact on numbers of ETPs. RNA-sequencing of the expanded ETPs in DKO mice revealed upregulation of HSC- and myeloid-associated transcriptional programs, reminiscent of ETP leukaemia e.g. Pbx1 (log2FC=3.0; p<0.0001) and Csf3r (log2FC=1.9; p=0.0038). Single-cell gene expression analysis confirmed co-expression of HSC and myeloid programs with lymphoid genes within individual DKO ETPs. Further, some key regulators of T-cell maturation which are aberrantly expressed in ETP leukemia were also disrupted in DKO ETPs e.g. Tcf7 (log2FC=-9.5; p<0.0001). Gene expression associated with aberrant Ras signalling was also present. However, despite a continued expansion of the ETP population with age, we did not observe leukemia in DKO mice with over 1 year of follow-up. Since ETP leukemias frequently feature activating mutations in genes regulating RAS signaling, we hypothesised that the expanded "pre-leukemic" ETPs in DKO mice would be primed for leukemic transformation by signalling pathway mutation. We therefore crossed DKO mice with a Flt3ITD/+ knock-in mouse line, as internal tandem duplications (ITD) of FLT3 are frequent in ETP leukemias. Ezh2fl/flRunx1fl/flRag1Cre+Flt3ITD/+ (DKOITD) mice showed dramatically reduced survival (median 9.3 weeks) resulting from an aggressive, fully penetrant acute leukemia showing a predominantly myeloid phenotype (e.g. Mac1) but with co-expression of some lymphoid antigens (e.g. intracellular CD3). Crucially, this leukaemia could be propagated in wild-type recipients upon transplantation of the expanded ETPs. DKOITD ETPs were transcriptionally very similar to DKO ETPs, retaining expression of lymphoid alongside HSC- and myeloid-associated genes. Finally, in a lympho-myeloid cell line model (EML cells) we demonstrated that Ezh2 inactivation-induced loss of H3K27me3 is associated with a corresponding increase in H3K27Ac, a transcriptional activating signal that recruits bromodomain proteins. As such, we reasoned that our ETP leukemia model might be sensitive to bromodomain inhibitors such as JQ1. Indeed, we observed high sensitivity of expanded DKOITD ETPs to JQ1, raising the possibility of a new therapeutic approach for ETP leukemias. This novel mouse model of ETP-propagated leukemia, driven by clinically relevant mutations, provides intriguing evidence that leukemias with a predominant myeloid phenotype, but co-expressing lymphoid genes, may initiate within a bona fide early lymphoid progenitor population. Since the functional characteristics of the cell of origin of a leukaemia may direct its progression and response to therapy, these findings could have important implications for future stratification and treatment of both AML and ETP leukemias. Disclosures No relevant conflicts of interest to declare.

A model for gene selection and classification of gene expression data

2007 ◽  
Vol 11 (2) ◽  
pp. 219-222 ◽  
Author(s):  
Mohd Saberi Mohamad ◽  
Sigeru Omatu ◽  
Safaai Deris ◽  
Siti Zaiton Mohd Hashim
Keyword(s):  
Gene Expression ◽  
Gene Expression Data ◽  
Gene Selection ◽  
Expression Data

Disease-Relevant Expression Of TRAF6 In Mouse HSC Results In An MDS-Like Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 101-101
Author(s):  
Jing Fang ◽  
Xiaona Liu ◽  
Brenden Barker ◽  
Lyndsey Bolanos ◽  
Yue Wei ◽  
...  
Keyword(s):  
Gene Expression ◽  
Conflicts Of Interest ◽  
Early Stage ◽  
Bone Marrow Failure ◽  
Gene Signature ◽  
Sublethal Dose ◽  
Hematopoietic Tissue ◽  
Hematopoietic Stem ◽  
Disease Evolution ◽  
Cd34 Cells

Abstract Overexpression of immune-related genes is widely reported in Myelodysplastic Syndrome (MDS), and chronic immune stimulation increases the risk for developing MDS. We find that TNF receptor associated factor 6 (TRAF6), an innate immune protein, is overexpressed approximately 2-fold in CD34+ cells from 40% of MDS patients, and may explain immune pathway activation in the MDS-initiating hematopoietic stem/progenitor cell (HSPC). In support of these observations and our hypothesis that TRAF6 is important in the pathophysiology of MDS, a gene expression analysis revealed that TRAF6 controls an MDS gene signature in human cells. We, and others, have previously shown that retroviral overexpression of TRAF6 in mouse HSPC results in MDS and Acute Myeloid Leukemia (AML). However, interpretations of these findings are hampered by supra-physiological levels of TRAF6 (>10-fold overexpression) and the stress associated with HSPC transduction/transplantation. To investigate the consequences of TRAF6 overexpression to MDS, we generated a transgenic mouse model overexpressing TRAF6 from a hematopoietic-specific Vav promoter. Expression of TRAF6 in HSPC was approximately 2-fold higher as compared to endogenous TRAF6 and in line with MDS patient CD34+ cells. By 15 months of age, half of Vav-TRAF6 mice succumbed to a hematologic disease resembling MDS associated with bone marrow failure (BMF). In contrast to the retroviral overexpression approach, Vav-TRAF6 mice did not develop AML. Examination of sick mice revealed stage-specific disease evolution. Initially, all Vav-TRAF6 mice exhibit an inversion of myeloid/lymphoid proportions. For Vav-TRAF6 mice that develop a fatal disease, they present with a hypocellular marrow, dysplasic myeloid cells, and neutropenia. A subset of mice also display anemia with nucleated red blood cells, poikilocytosis, and extramedullular erythropoiesis. In support of a BMF phenotype, HSPC from Vav-TRAF6 mice form fewer colonies in methylcellulose. To investigate the consequences of an acute exposure to pathogen, early-stage Vav-TRAF6 mice were treated with a single sublethal dose of lipopolysaccharide (LPS). Unlike wild-type (WT) mice, Vav-TRAF6 mice developed a rapid and reversible anemia, suggesting environmental factors can influence the severity of the disease. To gain insight into the mechanism contributing to BMF, gene expression profiling was performed in WT and Vav-TRAF6 HSPC. One of the enriched pathways consisted of AKT activation and FOXO downregulation. Consistent with the microarray analysis, AKT is constitutively phosphorylated at Thr308 in hematopoietic tissue from Vav-TRAF6 mice. SOD2, a transcriptional target of FoxO3a that is suppressed by activated AKT, is decreased in Vav-TRAF6 HSPC. Given that AKT/FOXO regulate reactive oxygen species (ROS) in cells, we investigated ROS levels in HPSC from Vav-TRAF6 and WT mice. Intracellular ROS is significantly elevated in BM cells from Vav-TRAF6 mice, and restored to normal levels when AKT was inhibited. In conclusion, we propose the potential role of TRAF6 in the development of MDS-associated BMF, partly due to constitutive activation of AKT and subsequent ROS elevation in HSPC cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Improving the Classification of Alzheimer’s Disease Using Hybrid Gene Selection Pipeline and Deep Learning

2021 ◽  
Vol 12 ◽  
Author(s):  
Nivedhitha Mahendran ◽  
P. M. Durai Raj Vincent ◽  
Kathiravan Srinivasan ◽  
Chuan-Yu Chang
Keyword(s):  
Gene Expression ◽  
Gene Selection ◽  
Imaging Techniques ◽  
Optimization Technique ◽  
Gene Expression Omnibus ◽  
Deep Belief Network ◽  
Bayesian Optimization ◽  
Belief Network ◽  
Feature Selection Techniques

Alzheimer’s is a progressive, irreversible, neurodegenerative brain disease. Even with prominent symptoms, it takes years to notice, decode, and reveal Alzheimer’s. However, advancements in technologies, such as imaging techniques, help in early diagnosis. Still, sometimes the results are inaccurate, which delays the treatment. Thus, the research in recent times focused on identifying the molecular biomarkers that differentiate the genotype and phenotype characteristics. However, the gene expression dataset’s generated features are huge, 1,000 or even more than 10,000. To overcome such a curse of dimensionality, feature selection techniques are introduced. We designed a gene selection pipeline combining a filter, wrapper, and unsupervised method to select the relevant genes. We combined the minimum Redundancy and maximum Relevance (mRmR), Wrapper-based Particle Swarm Optimization (WPSO), and Auto encoder to select the relevant features. We used the GSE5281 Alzheimer’s dataset from the Gene Expression Omnibus We implemented an Improved Deep Belief Network (IDBN) with simple stopping criteria after choosing the relevant genes. We used a Bayesian Optimization technique to tune the hyperparameters in the Improved Deep Belief Network. The tabulated results show that the proposed pipeline shows promising results.

scholarly journals Composition of Feature Relevancy Based Biomarker Gene Selection in Gene Expression Dataset

2019 ◽  
Vol 8 (4) ◽  
pp. 7480-7484
Keyword(s):  
Gene Expression ◽  
Information Theory ◽  
Gene Selection ◽  
Support Vector ◽  
Data Sets ◽  
Cancer Gene ◽  
Selection Technique ◽  
Gene Redundancy ◽  
Gene Data

Cancer gene selection plays a prominent work in the area of Bioinformatics. Gene selection methods aim to retain relevant genes and remove redundant genes. This proposed technique deals on gene selection techniques based on information theory. By investigating the information theory based on composition of feature relevancy, we consider that a excellent gene technique method could boost novel classification of the cancer gene data while reducing gene redundancy. Therefore, a modified gene selection technique called Composition of Feature Relevancy (CFR) is carried out. To assess CFR, the experiments are carrying out on five real-world cancer gene expression data sets and three best classifiers (KNN, Support Vector Machine and Random forest). The modified gene selection technique gives best outcome when competing to other recent technique in terms of accuracy and sensitivity in classification.

Genetic and cytokine profiles associated with symptomatic stage of CLL.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7062-7062
Author(s):  
Amit Balkrishna Agarwal ◽  
Laurence Cooke ◽  
Christopher Riley ◽  
David Mount ◽  
Daruka Mahadevan
Keyword(s):  
Gene Expression ◽  
Early Stage ◽  
Function Analysis ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Serum Cytokine ◽  
Hematopoietic Stem ◽  
Cytokine Profiles ◽  
High Stage ◽  
Cytokine Profiling

7062 Background: Pathogenesis of symptomatic CLL involves genetic changes associated with the CLL clone and changes within the microenvironment which contribute to chemo-resistance. To further understand these processes we compared early stage CLL to symptomatic late stage CLL using gene expression profiling as well as serum cytokine profiling for a better insight of the genetic and microenvironment changes associated with the most severe forms of the disease. Methods: We obtained pretreatment blood samples from CLL patients (10 low stage and 14 high stage) at the time of diagnosis. Patients were classified as low stage (Rai stage 0/I/II) and high stage (Rai stage III/IV). Gene expression profiles were obtained on a subset of patients using the HG-U133A 2.0 Affymetrix platform and analyzed for differential gene expression profiles. Serum from a subset of patients was used to perform cytokine profiling using the Raybiotech Cytokine Array platform (AAH-CYT-G1000) that allows for simultaneous measurement of >100 different cytokines. Results: Comparison of low versus high stage CLL revealed a set of 21 differentially expressed genes. 15 genes were up regulated in the high stage versus low stage, while 6 genes were down regulated. GO Molecular function analysis revealed that 9 of the 21 genes are involved in transcription factor activity. Other genes up regulated in the high stage group include CSNK1- shown to be involved in Myc derived oncogenesis and SETD8- a histone lysine methyltransferase previously implicated in several cancers. Serum cytokine profiles showed 6 cytokines to be significantly different in high stage patients. Two chemokines SDF-1/CXCL12 and uPAR known to be involved in stem cell mobilization and homing are increased in the serum of high stage patients. IGFBP-2, BMP-4 and MCP-4 were lower among high stage patients. Conclusions: Our study revealed a novel group of transcription factors are associated with higher stage CLL. Cytokine profiling showed increased levels of SDF-1/CXCL12, a chemokine that plays a key role in mobilization and homing of hematopoietic stem and CLL cells in high stage patients. Our study identifies putative therapeutic targets including CSNK1, SDF-1 and SETD8 for patients with high stage CLL.

The Microarray Signature of Rhesus Macaque CD34+CD123 (IL-3 Receptor)+ Hematopoietic Stem/Progenitor Cells Isolated Following Mobilization with Plerixafor Alone or in Combination with Granulocyte Colony-Stimulating Factor (G-CSF)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1301-1301
Author(s):  
Robert E. Donahue ◽  
Ping Jin ◽  
Johanna I. Klinman ◽  
Aylin C. Bonifacino ◽  
Mark E. Metzger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pathway Analysis ◽  
Rhesus Macaques ◽  
Receptor Activation ◽  
Mapk Signaling ◽  
Data Set ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Custom Made ◽  
Lymphoid Progenitors

Abstract Abstract 1301 CD34+ cells are a heterogeneous population of cells which contain the hematopoietic stem cell (HSC). Previously we determined that the microarray signature of CD34+ cells mobilized by G-CSF differed from those mobilized with either plerixafor (AMD3100) alone or in combination with G-CSF (Donahue RE, et al. Blood 2009; 114:2530–2541). Recently we also determined that a novel subpopulation of CD34+CD123+ cells was mobilized with plerixafor and not G-CSF in rhesus macaques (Uchida N, et al. Exp Hematol 2011; 39:795–805). To explore differences between CD34+CD123+ and CD34+CD123- cells, we evaluated their gene expression signatures. Following mobilization with plerixafor alone or in combination with G-CSF, we collected mononuclear cells by leukapheresis, isolated rhesus CD34+ cells by immunoselection, and further isolated CD34+CD123+ and CD34+CD123- by cell sorting. CD34+CD123+ cells were found not to express CXCR4 on their cell surface. Total RNA was isolated from cells and amplified to cRNA. Control cRNA was labeled with Cy3 dye and experimental cRNA was labeled with Cy5 dye. Control and experimental labeled cRNA were co-hybridized to a custom-made 17.5K cDNA (UniGene cluster) microarray. Gene expression was analyzed by quantifying the fluorescence from the microarray. The raw data set was filtered according to a standard procedure to exclude spots with minimum intensity. The relationship between the cells was analyzed using an unsupervised Eisen's hierarchical clustering method. Statistical analysis was done using Array Class Comparison analysis. Pathway analysis was carried out using Ingenuity Pathway Analysis. Principal Component Analysis demonstrated that CD34+CD123+ and CD34+CD123- cells cluster separately and are not distinguishable on the basis of mobilization regimen. Using Supervised Hierarchical Cluster Analysis for genes which were significantly different (p<0.05) there was further confirmation of clustering of the CD34+CD123+ cells versus the CD34+CD123- cells. Microarray analysis revealed that pathways including retinoic acid receptor activation and TGF-β and MAPK signaling were up-regulated in CD34+CD123+ cells, whereas glucocorticoid receptor and TREM-1 signaling, and genes involved in dendritic cell maturation and production of nitric oxide and reactive oxygen by macrophages were down regulated. The up regulated pathways and the down regulated pathways for the CD34+CD123+ population suggest that CD34+CD123+ cells are lymphoid progenitors. Upon comparing pathways between those previously reported to be unique to CD34+ cells mobilized with plerixafor alone or in combination with G-CSF, the majority are those that have been identified also to be in the CD34+CD123+ subpopulation. It appears as if the CD34+CD123+ population accounts for many of the differences in CD34+ cells mobilized with plerixafor observed in the earlier study. In conclusion, the microarray signature of the CD34+CD123+ cells subpopulation suggests that these cells are lymphoid progenitors which can be effectively mobilized with plerixafor. This may account for the more rapid lymphoid recovery we observed for rhesus macaques transplanted with CD34+ cells mobilized with plerixafor and suggests a therapeutic approach through immunoselection to selectively target CD34+CD123+ progenitor populations. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Menin regulates the function of hematopoietic stem cells and lymphoid progenitors

Blood ◽  
2009 ◽  
Vol 113 (8) ◽  
pp. 1661-1669 ◽  
Author(s):  
Ivan Maillard ◽  
Ya-Xiong Chen ◽  
Ann Friedman ◽  
Yuqing Yang ◽  
Anthony T. Tubbs ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Protein A ◽  
Suppressor Gene ◽  
Hematopoietic Stem ◽  
Lymphoid Progenitors ◽  
Functional Defect ◽  
B Lymphoid

Abstract Men1 is a tumor suppressor gene mutated in endocrine neoplasms. Besides its endocrine role, the Men1 gene product menin interacts with the mixed lineage leukemia (MLL) protein, a histone H3 lysine 4 methyltransferase. Although menin and MLL fusion proteins cooperate to activate Homeobox (Hox) gene expression during transformation, little is known about the normal hematopoietic functions of menin. Here, we studied hematopoiesis after Men1 ablation. Menin loss modestly impaired blood neutrophil, lymphocyte, and platelet counts. Without hematopoietic stress, multilineage and myelo-erythroid bone marrow progenitor numbers were preserved, while B lymphoid progenitors were decreased. In contrast, competitive transplantation revealed a marked functional defect of long-term hematopoietic stem cells (HSC) in the absence of menin, despite normal initial homing of progenitors to the bone marrow. HoxA9 gene expression was only modestly decreased in menin-deficient HSCs. These observations reveal a novel and essential role for menin in HSC homeostasis that was most apparent during situations of hematopoietic recovery, suggesting that menin regulates molecular pathways that are essential during the adaptive HSC response to stress.

scholarly journals Human myeloperoxidase gene expression in acute leukemia

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2096-2102 ◽  
Author(s):  
SR Zaki ◽  
GE Austin ◽  
D Swan ◽  
A Srinivasan ◽  
AH Ragab ◽  
...  
Keyword(s):  
Gene Expression ◽  
Early Stage ◽  
Leukemic Cells ◽  
Myeloid Differentiation ◽  
Cdna Clones ◽  
Oligonucleotide Probes ◽  
Acute Leukemias ◽  
Normal Bone ◽  
Myeloid Leukemias ◽  
The Relationship

Abstract To evaluate the relationship between myeloperoxidase (MPO) gene expression and specific lineages of hematopoietic differentiation, we analyzed expression of the MPO gene in a variety of normal and leukemic human cells. As a first step, we synthesized several oligonucleotide probes and isolated cDNA clones for the MPO gene. MPO expression was detected in most acute myeloid leukemias, and the level of expression correlated well with cytochemical enzymatic activity. No MPO message was detected in pure lymphoid leukemias, whereas very low basal levels of MPO transcripts were found in normal bone marrows. In four cases of acute undifferentiated leukemias cytochemically negative for MPO, significant levels of MPO transcripts were detected, suggesting a myeloid origin for these cases. These results indicate that MPO gene expression may serve as an additional marker for subclassification of acute leukemias and may be used to identify leukemic cells arrested at an early stage of the myeloid differentiation pathway.

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