C/EBPα in normal and malignant myelopoiesis

Friedman, Alan D.

doi:10.1007/s12185-015-1764-6

Cited by 91 publications

(83 citation statements)

References 153 publications

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“…5 This is suggestive of mutations differentially affecting DDX41 isoforms and may explain the selection for a D140 mutation hotspot as, in this scenario, it could result in isoform switching from the long form to the short form of DDX41, something which is commonly seen in germ line AML-predisposing CEBPA mutations. 16 The mean age of HM onset (62 years) of all cases to date emphasizes the importance of obtaining a family history and considering predisposition alleles in all adults with HMs. In addition, the younger age of diagnosis in missense mutant DDX41 families vs LOF mutants, is reminiscent of observations in GATA2 and RUNX1 families in which altered function of these mutant proteins more strongly predisposes to malignant progression.…”

Section: Resultsmentioning

confidence: 99%

Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies

Lewinsohn

Brown

Weinel

et al. 2016

Blood

191

176

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• Novel missense germ line DDX41 mutations define an earlier age of onset of hematologic malignancies than loss-of-function alleles.• Carriers of DDX41 germ line mutations usually have normal blood counts until a myeloid or lymphoid malignancy develops.Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical.

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Section: Resultsmentioning

confidence: 99%

Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies

Lewinsohn

Brown

Weinel

et al. 2016

Blood

191

176

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“…However, CEBPA is also implicated more broadly in hematopoiesis as a master TF (36,47,48), suggesting that its expression is temporally regulated to specify basophils and other terminal lineages (49). To test whether the +39-kb enhancer provides the temporal regulation of CEBPA expression for proper basophil differentiation, we performed directed differentiation of the CRISPR/Cas9 enhancer-mutagenized HSPCs in the presence of IL-3 (50-52).…”

Section: Basophil Associations Illuminate Mechanisms For Hematopoieticmentioning

confidence: 99%

Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

Guo

Nandakumar

Ulirsch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using highcoverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil countassociated locus near the master hematopoietic transcription factor CEBPA. The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.genome sequencing | GWAS | basophils | hematopoiesis | CEBPA

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“…Low levels of C/EBPa prevent GMP formation, whereas higher levels promote granulopoiesis over monopoiesis (25). C/EBPa induces miR-223 resulting in degradation of NFI-A mRNA to promote granulopoiesis (25). Both miR-21 and miR-196b promote the formation of monocytes while suppressing granulopoiesis (89).…”

Section: Mirnas Regulating Development Of Myeloid Cellsmentioning

confidence: 99%

miRNA in Macrophage Development and Function

Roy

2016

Antioxidants & Redox Signaling

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Significance: MicroRNAs (miRNAs) control cellular gene expression via primarily binding to 3¢ or 5¢ untranslated region of the target transcript leading to translational repression or mRNA degradation. In most cases, miRNAs have been observed to fine-tune the cellular responses and, therefore, act as a rheostat rather than an on/off switch. Transcription factor PU.1 is a master switch that controls monocyte/macrophage development from hematopoietic stem cells. Recent Advances: PU.1 induces a specific set of miRNAs while suppressing the miR17-92 cluster to regulate monocyte/macrophage development. In addition to development, miRNAs tightly control the macrophage polarization continuum from proinflammatory M1 or proreparative M2 by regulating expression of key transcription factors involved in the process of polarization. Critical Issues: miRNAs are intricately involved with fine-tuning fundamental macrophage functions such as phagocytosis, efferocytosis, inflammation, tissue repair, and tumor promotion. Macrophages are secretory cells that participate in intercellular communication by releasing regulatory molecules and microvesicles (MVs). MVs are bilayered lipid membranes packaging a hydrophilic cargo, including proteins and nucleic acids. Macrophage-derived MVs carry functionally active miRNAs that suppress gene expression in target cells via post-transcriptional gene silencing, thus regulating cell function. In summary, miRNAs fine-tune several major facets of macrophage development and function. Such fine-tuning is critical in preventing exaggerated macrophage response to endogenous or exogenous stimuli. Future Directions: A critical role of miRNAs in the regulation of innate immune response and macrophage biology, including development, differentiation, and activation, has emerged. A clear understanding of such regulation on macrophage function remains to be elucidated. Antioxid. Redox Signal. 25, 795-804.

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C/EBPα in normal and malignant myelopoiesis

Cited by 91 publications

References 153 publications

Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies

Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies

Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

miRNA in Macrophage Development and Function

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