Imprinted genes in myeloid lineage commitment in normal and malignant hematopoiesis

Benetatos, Leonidas; Vartholomatos, George

doi:10.1038/leu.2015.47

Cited by 8 publications

(10 citation statements)

References 146 publications

(147 reference statements)

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“…Finally, in our previous work we demonstrated that very small embryonic-like stem cells, which share several markers with migrating PGCs and express SexH receptors, can become specified into HSPCs [8,45,[53][54][55]. Whether some leukemias could originate in these developmentally primitive cells was recently hypothesized by another group, but requires further study [56].…”

Section: Discussionmentioning

confidence: 78%

Novel Evidence That Pituitary Gonadotropins Directly Stimulate Human Leukemic cells—studies on Myeloid Cell Lines and Primary Patient AML and CML Cells

Abdelbaset‐Ismail

Mierzejewska

Janowska‐Wieczorek

et al. 2014

Blood

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Background . It has been postulated that hematopoietic stem/progenitor cells (HSPCs) can become specified from a population of migrating primordial germ cells (PGCs) isolated from embryos. In support of this intriguing possibility, HSPCs and PGCs are both highly migratory populations of stem cells, and evidence has accumulated for the sharing of several mutated genes (e.g., Sall4) as well as chromosomal aberrations between germline tumors and leukemias or lymphomas, which suggests their common clonal origin. In fact, we recently observed that normal murine HSPCs express several functional receptors for pituitary gonadal hormones, such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL), in addition to gonadal hormones including estrogens, androgen, and progesterone. Of note, the plasma levels of FSH and LH are elevated in older patients, which correlate with an increase in the incidence of myeloid leukemia. Hypothesis . Based on this, we have hypothesized that gonadotropic hormones play a yet underappreciated role in human malignant hematopoiesis. Materials and Methods . To address this issue, we performed a complex series of experiments employing human myeloid hematopoietic cell lines (KG-1a, K-562, U937, THP-1, HEL) and primary patient cells (AML, CML) to address the influence of pituitary sex hormones (FSH, LH, PRL) as well as gonadal sex hormones (androgen, estrogen, progesterone) on proliferation, migration, and adhesion of malignant cells. In addition, expression of the corresponding receptors was evaluated at the mRNA level by PCR, and their functionality was confirmed by signaling studies based on phosphorylation of major signal transduction pathways (AKT, MAPKp42/44, STAT). Results. We demonstrate for the first time that human myeloid leukemia cell lines express all pituitary gonadotropin and several gonadal hormone receptors and that FSH and LH receptors are functional on these cells, as evaluated by chemotaxis and adhesion assays. Moreover, FSH and LH receptors were expressed and functional on patient leukemic blasts in bone marrow (BM) and peripheral blood (PB). Human leukemic cells from cell lines and primary patient-derived cells also expressed some other gonadal hormone receptors (PRL-R, estrogen, progesterone, and androgen receptors), albeit at lower levels. Moreover, we observed that several human myeloid cell lines as well as primary patient leukemic cells responded to sex hormones by proliferation. Conclusions . Our data are the first to indicate that pituitary-secreted gonadotropins stimulate migration, adhesion, and proliferation of leukemic cells. This latter effect seems to be direct, as the receptors for these hormones respond to stimulation by phosphorylation of intracellular pathways involved in cell proliferation. Established human myeloid leukemia cell lines and primary patient blasts also responded to stimulation by gonadal sex hormones. Finally, our studies provide further evidence supporting a developmental link between hematopoiesis and the germline. Disclosures No relevant conflicts of interest to declare.

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Section: Discussionmentioning

confidence: 78%

Novel Evidence That Pituitary Gonadotropins Directly Stimulate Human Leukemic cells—studies on Myeloid Cell Lines and Primary Patient AML and CML Cells

Abdelbaset‐Ismail

Mierzejewska

Janowska‐Wieczorek

et al. 2014

Blood

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“…Finally, in our previous work we demonstrated that very small embryonic-like stem cells, which share several markers with migrating PGCs and express SexH receptors, can become specified into HSPCs [ 8 , 45 , 53 – 55 ]. Whether some leukemias could originate in these developmentally primitive cells was recently hypothesized by another group, but requires further study [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Novel evidence that pituitary gonadotropins directly stimulate human leukemic cells-studies of myeloid cell lines and primary patient AML and CML cells

et al. 2015

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We recently reported that normal hematopoietic stem cells express functional pituitary sex hormone (SexH) receptors. Here we report for the first time that pituitary-secreted gonadotrophins stimulate migration, adhesion, and proliferation of several human myeloid and lymphoid leukemia cell lines. Similar effects were observed after stimulation of human leukemic cell lines by gonadal SexHs. This effect seems to be direct, as the SexH receptors expressed by leukemic cells responded to stimulation by phosphorylation of MAPKp42/44 and AKTser473. Furthermore, in parallel studies we confirmed that human primary patient-derived AML and CML blasts also express several functional SexH receptors. These results shed more light on the potential role of SexHs in leukemogenesis and, in addition, provide further evidence suggesting a developmental link between hematopoiesis and the germline.

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“…These regions, known as differentially methylated regions (DMRs), exhibit unique patterns of methylation at CG cytosine residues based on the parental origin of the chromosome. The temporo-spatial dosage of imprinted genes governed by genomic imprinting is integral to proper growth and development, and its dysregulation is found in several developmental abnormalities [2] and malignancies such as leukemia [3].…”

Section: Introductionmentioning

confidence: 99%

Increased methylation upstream of the MEG3 promotor is observed in acute myeloid leukemia patients with better overall survival

et al. 2019

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BackgroundThe delta-like non-canonical Notch ligand 1 (DLK1)-maternally expressed 3(MEG3) locus (DLK1-MEG3 locus) plays a critical role in the maintenance and differentiation of hematopoietic stem cells. Accumulating evidence implicates the imprinted genes from this locus, DLK1 and MEG3, in the development and progression of acute myeloid leukemia (AML). However, the contribution of this locus to the treatment response of patients and their survival is unknown.MethodsDNA methylation of select CG dinucleotide-containing amplicons (CpG sites) within the DLK1-MEG3 locus and within differentially methylated regions of other imprinted loci was assessed in the mononuclear cells of 45 AML patients by combined bisulfite restriction analysis. Methylation results were compared with patient response to first-round induction therapy and overall survival. Multivariable analysis was employed to identify independent prognostic factors for patient overall survival in AML.ResultsIncreased methylation at CpG sites within the MEG3 promotor region was observed in AML patients having longer overall survival. In addition, patients with shorter overall survival had increased expression of DLK1 and MEG3, and methylation at the MEG3-DMR CpG site inversely correlated with MEG3 expression. Multivariable analysis revealed that methylation at CG9, a non-imprinted CpG site within the MEG3 promotor region which contains a CCCTC-binding factor (CTCF)-binding DNA sequence, is an independent prognostic factor for the overall survival of AML patients.ConclusionsThe results of our pilot study underscore the importance of the DLK1-MEG3 locus in AML development and progression. We identify CG9 methylation as an independent prognostic factor for AML patient survival, which suggests that distinct miRNA signatures from the DLK1-MEG3 locus could reflect varying degrees of cell stemness and present novel opportunities for personalized therapies in the future. These data provide a foundation for future studies into the role of higher-order chromatin structure at DLK1-MEG3 in AML.Electronic supplementary materialThe online version of this article (10.1186/s13148-019-0643-z) contains supplementary material, which is available to authorized users.

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Imprinted genes in myeloid lineage commitment in normal and malignant hematopoiesis

Cited by 8 publications

References 146 publications

Novel Evidence That Pituitary Gonadotropins Directly Stimulate Human Leukemic cells—studies on Myeloid Cell Lines and Primary Patient AML and CML Cells

Novel Evidence That Pituitary Gonadotropins Directly Stimulate Human Leukemic cells—studies on Myeloid Cell Lines and Primary Patient AML and CML Cells

Novel evidence that pituitary gonadotropins directly stimulate human leukemic cells-studies of myeloid cell lines and primary patient AML and CML cells

Increased methylation upstream of the MEG3 promotor is observed in acute myeloid leukemia patients with better overall survival

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