HemaExplorer: a Web server for easy and fast visualization of gene expression in normal and malignant hematopoiesis

Bagger, Frederik Otzen; Rapin, Nicolas; Theilgaard‐Mönch, Kim; Kaczkowski, Bogumił; Jendholm, Johan; Winther, Ole; Porse, Bo T.

doi:10.1182/blood-2012-05-427310

Cited by 35 publications

(31 citation statements)

References 10 publications

(18 reference statements)

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“…The reduced sensitivity may be due to the fact that hematopoietic progenitor cells dispose lower GLI1 and GLI2 expression levels compared with AML cells as observed in our own data and also published by others (36). Furthermore, these observations are in line with data published on B-CLL where normal B lymphocytes showed less sensitivity toward GANT61 treatment than primary CLL cells (30).…”

Section: Discussionsupporting

confidence: 82%

Expression of Hedgehog Pathway Mediator GLI Represents a Negative Prognostic Marker in Human Acute Myeloid Leukemia and Its Inhibition Exerts Antileukemic Effects

Wellbrock

Latuske

Köhler

et al. 2015

Clinical Cancer Research

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Purpose: The Hedgehog pathway plays an important role in stem-cell biology and malignant transformation. Therefore, we investigated the expression and prognostic impact of Hedgehog pathway members in acute myeloid leukemia (AML).Experimental Design: Pretreatment samples from 104 newly diagnosed AML patients (AMLSG 07-04 trial) were analyzed by qPCR, and expression of Hedgehog family members was correlated with clinical outcome. Inhibition of GLI by GANT61 or shRNA was investigated in AML cells in vitro and in vivo.Results: Expression of receptors Smoothened and Patched-1 and their downstream mediators, GLI1, GLI2, and GLI3, was found in AML patients in contrast to Hedgehog ligands. GLI2 expression had a significant negative influence on event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS; P ¼ 0.037, 0.026, and 0.013, respectively) and was correlated with FLT3 mutational status (P < 0.001). Analysis of a second, independent patient cohort confirmed the negative impact of GLI2 on EFS and OS (P ¼ 0.007 and 0.003, respectively; n ¼ 290). Within this cohort, GLI1 had a negative prognostic impact (P < 0.001 for both EFS and OS). Although AML cells did not express Hedgehog ligands by qPCR, AML patients had significantly increased Desert Hedgehog (DHH) plasma levels compared with healthy subjects (P ¼ 0.002), in whom DHH was presumably provided by bone marrow niche cells. Moreover, the GLI inhibitor GANT61 or knockdown of GLI1/2 by shRNA caused antileukemic effects, including induction of apoptosis, reduced proliferation, and colony formation in AML cells, and a survival benefit in mice.Conclusions: GLI expression is a negative prognostic factor and might represent a novel druggable target in AML. Clin Cancer Res; 21(10); 2388-98. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 82%

Expression of Hedgehog Pathway Mediator GLI Represents a Negative Prognostic Marker in Human Acute Myeloid Leukemia and Its Inhibition Exerts Antileukemic Effects

Wellbrock

Latuske

Köhler

et al. 2015

Clinical Cancer Research

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“…28,29,31 We therefore used HemaExplorer (http://servers.binf.ku.dk/hemaexplorer/), an online database of gene expression profiles, to assess its expression TGIF1 is a negative regulator of MLL-rearranged leukemia A Willer et al patterns in normal and malignant human hematopoietic cells. 46,47 Focusing on myeloid development, we find TGIF1 expression to be low in HSCs and upregulated in committed progenitors (common myeloid progenitor, granulocyte-monocyte progenitor, megakaryocyte-erythroid progenitor) and maintained or downregulated, respectively, as these progenitors differentiate towards monocytes and granulocytes ( Figure 1a). Moreover, using the cancer vs nearest normal feature of HemaExplorer (a bioinformatics tool that allows the user to (1) identify the closest normal counterpart to AML cells and (2) determine the expression of input genes in AML cells relative to this normal counterpart), we find that the expression of TGIF1 is selectively downregulated in MLL-rearranged AML in a data set with information on four distinct subtypes of aberrant karyotype AML (Figure 1b).…”

Section: Resultsmentioning

confidence: 93%

TGIF1 is a negative regulator of MLL-rearranged acute myeloid leukemia

et al. 2014

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Members of the TALE (three-amino-acid loop extension) family of atypical homeodomain-containing transcription factors are important downstream effectors of oncogenic fusion proteins involving the mixed lineage leukemia (MLL) gene. A well-characterized member of this protein family is MEIS1, which orchestrates a transcriptional program required for the maintenance of MLL-rearranged acute myeloid leukemia (AML). TGIF1/TGIF2 are relatively uncharacterized TALE transcription factors, which, in contrast to the remaining family, have been shown to act as transcriptional repressors. Given the general importance of this family in malignant hematopoiesis, we therefore tested the potential function of TGIF1 in the maintenance of MLL-rearranged AML. Gene expression analysis of MLL-rearranged patient blasts demonstrated reduced TGIF1 levels, and, in accordance, we find that forced expression of TGIF1 in MLL-AF9-transformed cells promoted differentiation and cell cycle exit in vitro, and delayed leukemic onset in vivo. Mechanistically, we show that TGIF1 interferes with a MEIS1-dependent transcriptional program by associating with MEIS1-bound regions in a competitive manner and that the MEIS1:TGIF1 ratio influence the clinical outcome. Collectively, these findings demonstrate that TALE family members can act both positively and negatively on transcriptional programs responsible for leukemic maintenance and provide novel insights into the regulatory gene expression circuitries in MLL-rearranged AML.

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“…At page 10 we describe data in two other NK AML datasets generated by the Bullinger lab indicating that high ELMO1 expression also predicts poor prognosis in these datasets and these data were already included in the Supplemental files of our previous paper [18]. Data for Figure S1B was derived from the HemaExplorer database (http://servers.binf.ku.dk/hemaexplorer/) [30]. For Figure S1C we used data from the Noverhstern lab [31].…”

Section: Methodsmentioning

confidence: 99%

ELMO1 Is Upregulated in AML CD34+ Stem/Progenitor Cells, Mediates Chemotaxis and Predicts Poor Prognosis in Normal Karyotype AML

2014

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Both normal as well leukemic hematopoietic stem cells critically depend on their microenvironment in the bone marrow for processes such as self-renewal, survival and differentiation, although the exact pathways that are involved remain poorly understood. We performed transcriptome analysis on primitive CD34+ acute myeloid leukemia (AML) cells (n = 46), their more differentiated CD34− leukemic progeny, and normal CD34+ bone marrow cells (n = 31) and focused on differentially expressed genes involved in adhesion and migration. Thus, Engulfment and Motility protein 1 (ELMO1) was identified amongst the top 50 most differentially expressed genes. ELMO1 is a crucial link in the signaling cascade that leads to activation of RAC GTPases and cytoskeleton rearrangements. We confirmed increased ELMO1 expression at the mRNA and protein level in a panel of AML samples and showed that high ELMO1 expression is an independent negative prognostic factor in normal karyotype (NK) AML in three large independent patient cohorts. Downmodulation of ELMO1 in human CB CD34+ cells did not significantly alter expansion, progenitor frequency or differentiation in stromal co-cultures, but did result in a decreased frequency of stem cells in LTC-IC assays. In BCR-ABL-transduced human CB CD34+ cells depletion of ELMO1 resulted in a mild decrease in proliferation, but replating capacity of progenitors was severely impaired. Downregulation of ELMO1 in a panel of primary CD34+ AML cells also resulted in reduced long-term growth in stromal co-cultures in two out of three cases. Pharmacological inhibition of the ELMO1 downstream target RAC resulted in a severely impaired proliferation and survival of leukemic cells. Finally, ELMO1 depletion caused a marked decrease in SDF1-induced chemotaxis of leukemic cells. Taken together, these data show that inhibiting the ELMO1-RAC axis might be an alternative way to target leukemic cells.

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HemaExplorer: a Web server for easy and fast visualization of gene expression in normal and malignant hematopoiesis

Cited by 35 publications

References 10 publications

Expression of Hedgehog Pathway Mediator GLI Represents a Negative Prognostic Marker in Human Acute Myeloid Leukemia and Its Inhibition Exerts Antileukemic Effects

Expression of Hedgehog Pathway Mediator GLI Represents a Negative Prognostic Marker in Human Acute Myeloid Leukemia and Its Inhibition Exerts Antileukemic Effects

TGIF1 is a negative regulator of MLL-rearranged acute myeloid leukemia

ELMO1 Is Upregulated in AML CD34+ Stem/Progenitor Cells, Mediates Chemotaxis and Predicts Poor Prognosis in Normal Karyotype AML

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