Novel regulators in hematopoietic stem cells can be revealed by a functional approach under leukemic condition

Cheng, Hui; Liu, Y; Jia, Qiong; Ma, Shihui; Yuan, Weiping; Jia, Haibo; Cheng, Tao

doi:10.1038/leu.2016.118

Cited by 6 publications

(13 citation statements)

References 13 publications

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“…As done in our previous research, we profiled the gene expressions in BM HSCs (from control and leukemia mice) at different time points (Day 7, Day 10 and Day 14) and screened the differentially expressed genes [ 7 , 8 ]. Since highly-expressed genes were usually regarded as having biological importance [ 14 ], we highlighted Maff and Egr3 as they were among the most highly expressed (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Since highly-expressed genes were usually regarded as having biological importance [ 14 ], we highlighted Maff and Egr3 as they were among the most highly expressed (Fig. 1a ) and their functional roles in HSCs under leukemia were less known [ 7 , 8 ]. The high expressions of the two genes in HSCs were validated using quantitative reverse-transcription PCR (qRT-PCR) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Microarray of gene expressions in the CD45.1 + LKS + cells was performed at CapitalBio in Beijing. Procedures for total RNA extraction, cRNA amplification, labeling, and hybridization, as well as RNA quality confirmation, were implemented according to protocols that we described previously [ 7 , 8 ]. Raw data normalization and analysis of differentially-expressed genes were done using Microarray Analysis Software v5.0 (Affymetrix).…”

Section: Methodsmentioning

confidence: 99%

“…pro-proliferation); and Egr3 potently suppressed cell cycle (i.e. counter-proliferation) [ 7 , 8 ]. In addition, we found via molecular profiling that Egr3 up-regulated p18 and p19 , two cyclin-dependent kinase inhibitors (CKIs), which might be how Egr3 suppressed cell cycle [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…First, we use information of molecular interactions to indicate possible actions related to Maff / Egr3 . Second, we numerically test the possibilities with experimental data of HSC cell cycle [ 7 , 8 ]. The tests are implemented on a curated cell cycle dynamic model with organism comparability to our experimental data [ 11 – 13 ], aiming to find out the ways of actions giving rise to the particular kinetic phenomena observed in the experiments.…”

Section: Introductionmentioning

confidence: 99%

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System modeling reveals the molecular mechanisms of HSC cell cycle alteration mediated by Maff and Egr3 under leukemia

Yin

Cheng

et al. 2017

BMC Syst Biol

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BackgroundMolecular mechanisms of the functional alteration of hematopoietic stem cells (HSCs) in leukemic environment attract intensive research interests. As known in previous researches, Maff and Egr3 are two important genes having opposite functions on cell cycle; however, they are both highly expressed in HSCs under leukemia. Hence, exploring the molecular mechanisms of how the genes act on cell cycle will help revealing the functional alteration of HSCs.ResultsWe herein utilize the bioinformatic resources to computationally model the acting mechanisms of Maff and Egr3 on cell cycle. Using the data of functional experiments as reference, molecular acting mechanisms are optimally enumerated through model selection. The results are consolidated by evidences from gene sequence analysis, thus having enhanced the confidence of our pilot findings, which suggest that HSCs possibly undergo a “adaptation - suppression” process in response to the malignant environment of leukemia.ConclusionAs a pilot research, our results may provide valuable insights for further experimental studies. Meanwhile, our research method combining computational modeling and data from functional experiments can be worthwhile for knowledge discovery; and it can be generalized and extended to other biological/biomedical studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-017-0467-4) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

System modeling reveals the molecular mechanisms of HSC cell cycle alteration mediated by Maff and Egr3 under leukemia

Yin

Cheng

et al. 2017

BMC Syst Biol

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Hematopoiesis and microenvironment in hematological malignancies

2018

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Adult hematopoietic stem cells (HSCs) and progenitors (HPCs) reside in the bone marrow, a highly orchestrated architecture. In the bone marrow, the process of how HSCs exert self-renewal and differentiation is tightly regulated by the surrounding microenvironment, or niche. Recent advances in imaging technologies and numerous knockout or knockin mouse models have greatly improved our understanding of the organization of the bone marrow niche. This niche compartment includes a complex network of mesenchymal stem cells (MSC), osteolineage cells, endothelial cells (arterioles and sinusoids), sympathetic nerves, nonmyelinating Schwann cells and megakaryocytes. In addition, different types of mediators, such as cytokines/chemokines, reactive oxygen species (ROS) and exosomes play a pivotal role in regulating the function of hematopoietic cells. Therefore, the niche components and the hematopoietic system make up an ecological environment that maintains the homeostasis and responds to stress, damage or disease conditions. On the other hand, the niche compartment can become a traitor that can do harm to normal hematopoietic cells under pathological conditions. Studies on the diseased bone marrow niche have only recently begun to appear in the extant literature. In this short review, we discuss the most recent advances regarding the behaviors of normal hematopoietic cells and their niche alterations in hematological malignancies.

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Increased expression of RUNX3 inhibits normal human myeloid development

et al. 2022

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RUNX3 is a transcription factor dysregulated in acute myeloid leukemia (AML). However, its role in normal myeloid development and leukemia is poorly understood. Here we investigate RUNX3 expression in both settings and the impact of its dysregulation on myelopoiesis. We found that RUNX3 mRNA expression was stable during hematopoiesis but decreased with granulocytic differentiation. In AML, RUNX3 mRNA was overexpressed in many disease subtypes, but downregulated in AML with core binding factor abnormalities, such as RUNX1::ETO. Overexpression of RUNX3 in human hematopoietic stem and progenitor cells (HSPC) inhibited myeloid differentiation, particularly of the granulocytic lineage. Proliferation and myeloid colony formation were also inhibited. Conversely, RUNX3 knockdown did not impact the myeloid growth and development of human HSPC. Overexpression of RUNX3 in the context of RUNX1::ETO did not rescue the RUNX1::ETO-mediated block in differentiation. RNA-sequencing showed that RUNX3 overexpression downregulates key developmental genes, such as KIT and RUNX1, while upregulating lymphoid genes, such as KLRB1 and TBX21. Overall, these data show that increased RUNX3 expression observed in AML could contribute to the developmental arrest characteristic of this disease, possibly by driving a competing transcriptional program favoring a lymphoid fate.

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Novel regulators in hematopoietic stem cells can be revealed by a functional approach under leukemic condition

Cited by 6 publications

References 13 publications

System modeling reveals the molecular mechanisms of HSC cell cycle alteration mediated by Maff and Egr3 under leukemia

System modeling reveals the molecular mechanisms of HSC cell cycle alteration mediated by Maff and Egr3 under leukemia

Hematopoiesis and microenvironment in hematological malignancies

Increased expression of RUNX3 inhibits normal human myeloid development

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