Transcriptomic Analysis Identifies RNA Binding Proteins as Putative Regulators of Myelopoiesis and Leukemia
Acute myeloid leukemia (AML) is a common and aggressive hematological malignancy. Acquisition of heterogeneous genetic aberrations and epigenetic dysregulation lead to the transformation of hematopoietic stem cells (HSC) into leukemic stem cells (LSC), which subsequently gives rise to immature blast...
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Frontiers Media S.A.
2019-08-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2019.00692/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
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DOAJ |
author |
Subha Saha Krushna Chandra Murmu Mayukh Biswas Sohini Chakraborty Jhinuk Basu Swati Madhulika Srinivasa Prasad Kolapalli Santosh Chauhan Amitava Sengupta Punit Prasad |
spellingShingle |
Subha Saha Krushna Chandra Murmu Mayukh Biswas Sohini Chakraborty Jhinuk Basu Swati Madhulika Srinivasa Prasad Kolapalli Santosh Chauhan Amitava Sengupta Punit Prasad Transcriptomic Analysis Identifies RNA Binding Proteins as Putative Regulators of Myelopoiesis and Leukemia Frontiers in Oncology RNA binding proteins (RBP) myeloid development acute myeloid leukemia (AML) hematopoietic stem cells leukemic stem cells |
author_facet |
Subha Saha Krushna Chandra Murmu Mayukh Biswas Sohini Chakraborty Jhinuk Basu Swati Madhulika Srinivasa Prasad Kolapalli Santosh Chauhan Amitava Sengupta Punit Prasad |
author_sort |
Subha Saha |
title |
Transcriptomic Analysis Identifies RNA Binding Proteins as Putative Regulators of Myelopoiesis and Leukemia |
title_short |
Transcriptomic Analysis Identifies RNA Binding Proteins as Putative Regulators of Myelopoiesis and Leukemia |
title_full |
Transcriptomic Analysis Identifies RNA Binding Proteins as Putative Regulators of Myelopoiesis and Leukemia |
title_fullStr |
Transcriptomic Analysis Identifies RNA Binding Proteins as Putative Regulators of Myelopoiesis and Leukemia |
title_full_unstemmed |
Transcriptomic Analysis Identifies RNA Binding Proteins as Putative Regulators of Myelopoiesis and Leukemia |
title_sort |
transcriptomic analysis identifies rna binding proteins as putative regulators of myelopoiesis and leukemia |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2019-08-01 |
description |
Acute myeloid leukemia (AML) is a common and aggressive hematological malignancy. Acquisition of heterogeneous genetic aberrations and epigenetic dysregulation lead to the transformation of hematopoietic stem cells (HSC) into leukemic stem cells (LSC), which subsequently gives rise to immature blast cells and a leukemic phenotype. LSCs are responsible for disease relapse as current chemotherapeutic regimens are not able to completely eradicate these cellular sub-populations. Therefore, it is critical to improve upon the existing knowledge of LSC specific markers, which would allow for specific targeting of these cells more effectively allowing for their sustained eradication from the cellular milieu. Although significant milestones in decoding the aberrant transcriptional network of various cancers, including leukemia, have been achieved, studies on the involvement of post-transcriptional gene regulation (PTGR) in disease progression are beginning to unfold. RNA binding proteins (RBPs) are key players in mediating PTGR and they regulate the intracellular fate of individual transcripts, from their biogenesis to RNA metabolism, via interactions with RNA binding domains (RBDs). In this study, we have used an integrative approach to systematically profile RBP expression and identify key regulatory RBPs involved in normal myeloid development and AML. We have analyzed RNA-seq datasets (GSE74246) of HSCs, common myeloid progenitors (CMPs), granulocyte-macrophage progenitors (GMPs), monocytes, LSCs, and blasts. We observed that normal and leukemic cells can be distinguished on the basis of RBP expression, which is indicative of their ability to define cellular identity, similar to transcription factors. We identified that distinctly co-expressing modules of RBPs and their subclasses were enriched in hematopoietic stem/progenitor (HSPCs) and differentiated monocytes. We detected expression of DZIP3, an E3 ubiquitin ligase, in HSPCs, knockdown of which promotes monocytic differentiation in cell line model. We identified co-expression modules of RBP genes in LSCs and among these, distinct modules of RBP genes with high and low expression. The expression of several AML-specific RBPs were also validated by quantitative polymerase chain reaction. Network analysis identified densely connected hubs of ribosomal RBP genes (rRBPs) with low expression in LSCs, suggesting the dependency of LSCs on altered ribosome dynamics. In conclusion, our systematic analysis elucidates the RBP transcriptomic landscape in normal and malignant myelopoiesis, and highlights the functional consequences that may result from perturbation of RBP gene expression in these cellular landscapes. |
topic |
RNA binding proteins (RBP) myeloid development acute myeloid leukemia (AML) hematopoietic stem cells leukemic stem cells |
url |
https://www.frontiersin.org/article/10.3389/fonc.2019.00692/full |
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doaj-30803bc55e61450d97dcef14d86a83552020-11-25T02:33:13ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-08-01910.3389/fonc.2019.00692468213Transcriptomic Analysis Identifies RNA Binding Proteins as Putative Regulators of Myelopoiesis and LeukemiaSubha Saha0Krushna Chandra Murmu1Mayukh Biswas2Sohini Chakraborty3Jhinuk Basu4Swati Madhulika5Srinivasa Prasad Kolapalli6Santosh Chauhan7Amitava Sengupta8Punit Prasad9Epigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, IndiaEpigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, IndiaTranslational Research Unit of Excellence (TRUE), Stem Cell and Leukemia Laboratory, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), Kolkata, IndiaDepartment of Pathology, New York University School of Medicine, New York, NY, United StatesEpigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, IndiaEpigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, IndiaCell Biology and Infectious Disease Unit, Institute of Life Sciences, Bhubaneswar, IndiaCell Biology and Infectious Disease Unit, Institute of Life Sciences, Bhubaneswar, IndiaTranslational Research Unit of Excellence (TRUE), Stem Cell and Leukemia Laboratory, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), Kolkata, IndiaEpigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, IndiaAcute myeloid leukemia (AML) is a common and aggressive hematological malignancy. Acquisition of heterogeneous genetic aberrations and epigenetic dysregulation lead to the transformation of hematopoietic stem cells (HSC) into leukemic stem cells (LSC), which subsequently gives rise to immature blast cells and a leukemic phenotype. LSCs are responsible for disease relapse as current chemotherapeutic regimens are not able to completely eradicate these cellular sub-populations. Therefore, it is critical to improve upon the existing knowledge of LSC specific markers, which would allow for specific targeting of these cells more effectively allowing for their sustained eradication from the cellular milieu. Although significant milestones in decoding the aberrant transcriptional network of various cancers, including leukemia, have been achieved, studies on the involvement of post-transcriptional gene regulation (PTGR) in disease progression are beginning to unfold. RNA binding proteins (RBPs) are key players in mediating PTGR and they regulate the intracellular fate of individual transcripts, from their biogenesis to RNA metabolism, via interactions with RNA binding domains (RBDs). In this study, we have used an integrative approach to systematically profile RBP expression and identify key regulatory RBPs involved in normal myeloid development and AML. We have analyzed RNA-seq datasets (GSE74246) of HSCs, common myeloid progenitors (CMPs), granulocyte-macrophage progenitors (GMPs), monocytes, LSCs, and blasts. We observed that normal and leukemic cells can be distinguished on the basis of RBP expression, which is indicative of their ability to define cellular identity, similar to transcription factors. We identified that distinctly co-expressing modules of RBPs and their subclasses were enriched in hematopoietic stem/progenitor (HSPCs) and differentiated monocytes. We detected expression of DZIP3, an E3 ubiquitin ligase, in HSPCs, knockdown of which promotes monocytic differentiation in cell line model. We identified co-expression modules of RBP genes in LSCs and among these, distinct modules of RBP genes with high and low expression. The expression of several AML-specific RBPs were also validated by quantitative polymerase chain reaction. Network analysis identified densely connected hubs of ribosomal RBP genes (rRBPs) with low expression in LSCs, suggesting the dependency of LSCs on altered ribosome dynamics. In conclusion, our systematic analysis elucidates the RBP transcriptomic landscape in normal and malignant myelopoiesis, and highlights the functional consequences that may result from perturbation of RBP gene expression in these cellular landscapes.https://www.frontiersin.org/article/10.3389/fonc.2019.00692/fullRNA binding proteins (RBP)myeloid developmentacute myeloid leukemia (AML)hematopoietic stem cellsleukemic stem cells |