Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF–triggered granulopoiesis

Skokowa, Julia; Klimiankou, Maxim; Klimenkova, Olga; Lan, Dan; Gupta, Kshama; Hussein, Kais; Carrizosa, Esteban; Kusnetsova, I.; Li, Zhixiong; Sustmann, Claudio; Ganser, Arnold; Zeidler, Cornelia; Kreipe, Hans-Heinrich; Burkhardt, Janis K.; Grosschedl, Rudolf; Welte, Karl

doi:10.1038/nm.2958

Cited by 70 publications

(80 citation statements)

References 54 publications

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“…Previous studies on Lef1 have largely been restricted to its role in lymphoid lineages, where it has been shown to have a function in T cell development and to affect proliferation and apoptosis in pro-B cells (11). However, it also plays a pivotal role in granulopoiesis, and recent data suggest a more complex role in hematopoiesis (12,32,33).…”

Section: Resultsmentioning

confidence: 99%

C/EBPa-Mediated Activation of MicroRNAs 34a and 223 Inhibits Lef1 Expression To Achieve Efficient Reprogramming into Macrophages

Rodríguez-Ubreva

Ciudad

Oevelen

et al. 2014

Molecular and Cellular Biology

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d MicroRNAs (miRNAs) exert negative effects on gene expression and influence cell lineage choice during hematopoiesis. C/EBPainduced pre-B cell-to-macrophage transdifferentiation provides an excellent model to investigate the contribution of miRNAs to hematopoietic cell identity, especially because the two cell types involved fall into separate lymphoid and myeloid branches. In this process, efficient repression of the B cell-specific program is essential to ensure transdifferentation and macrophage function. miRNA profiling revealed that upregulation of miRNAs is highly predominant compared with downregulation and that C/EBPa directly regulates several upregulated miRNAs. We also determined that miRNA 34a (miR-34a) and miR-223 sharply accelerate C/EBPa-mediated transdifferentiation, whereas their depletion delays this process. These two miRNAs affect the transdifferentiation efficiency and activity of macrophages, including their lipopolysaccharide (LPS)-dependent inflammatory response. miR-34a and miR-223 directly target and downregulate the lymphoid transcription factor Lef1, whose ectopic expression delays transdifferentiation to an extent similar to that seen with miR-34a and miR-223 depletion. In addition, ectopic introduction of Lef1 in macrophages causes upregulation of B cell markers, including CD19, Pax5, and Ikzf3. Our report demonstrates the importance of these miRNAs in ensuring the erasure of key B cell transcription factors, such as Lef1, and reinforces the notion of their essential role in fine-tuning the control required for establishing cell identity.

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Section: Resultsmentioning

confidence: 99%

C/EBPa-Mediated Activation of MicroRNAs 34a and 223 Inhibits Lef1 Expression To Achieve Efficient Reprogramming into Macrophages

Rodríguez-Ubreva

Ciudad

Oevelen

et al. 2014

Molecular and Cellular Biology

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“…Previously, we found that hematopoietic-specific interaction partner of HAX1, HCLS1 protein, was downregulated in myeloid cells of CN patients. 40 Therefore, we next analyzed whether diminished levels of HAX1 or HCLS1 led to inhibition of SLPI levels. Indeed, we found that SLPI mRNA expression was markedly reduced in NB4 cells transduced with HAX1 or HCLS1 shRNA constructs, in comparison with controlshRNA-transduced cells ( Figure 3E).…”

Section: Feedback Regulation Of Slpi By Nementioning

confidence: 99%

A lack of secretory leukocyte protease inhibitor (SLPI) causes defects in granulocytic differentiation

Klimenkova¹,

Ellerbeck²,

Klimiankou³

et al. 2014

Blood

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Key Points• The natural inhibitor of neutrophil elastase, SLPI, is severely reduced in severe congenital neutropenia patients.• SLPI controls myeloid differentiation by regulation of NFkB, ERK1/2:LEF-1, and c-myc activation.We identified diminished levels of the natural inhibitor of neutrophil elastase (NE), secretory leukocyte protease inhibitor (SLPI), in myeloid cells and plasma of patients with severe congenital neutropenia (CN). We further found that downregulation of SLPI in CD34 1 bone marrow (BM) hematopoietic progenitors from healthy individuals resulted in markedly reduced in vitro myeloid differentiation accompanied by cell-cycle arrest and elevated apoptosis. Reciprocal regulation of SLPI by NE is well documented, and we previously demonstrated diminished NE levels in CN patients. Here, we found that transduction of myeloid cells with wild-type NE or treatment with exogenous NE increased SLPI messenger RNA and protein levels, whereas transduction of mutant forms of NE or inhibition of NE resulted in downregulation of SLPI. An analysis of the mechanisms underlying the diminished myeloid differentiation caused by reduced SLPI levels revealed that downregulation of SLPI with short hairpin RNA (shRNA) upregulated nuclear factor kB levels and reduced phospho-extracellular signal-regulated kinase (ERK1/2)-mediated phosphorylation and activation of the transcription factor lymphoid enhancer-binding factor-1 (LEF-1). Notably, microarray analyses revealed severe defects in signaling cascades regulating the cell cycle, including c-Myc-downstream signaling, in myeloid cells transduced with SLPI shRNA. Taken together, these results indicate that SLPI controls the proliferation, differentiation, and cell cycle of myeloid cells. (Blood. 2014;123(8):1239-1249

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“…It is unclear how these single point mutations affect the function of the protein and the viability of phagocytes. Some data suggest that ELANE gene mutations are not sufficient to cause the SCN phenotype and other genes may act as modifiers on promyelocyte survival and their response to G-CSF (9)(10)(11). There is also an absence of correlation between the genotype and phenotype.…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells

Nayak¹,

Trump²,

Aronow³

et al. 2015

J. Clin. Invest.

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Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF–triggered granulopoiesis

Cited by 70 publications

References 54 publications

C/EBPa-Mediated Activation of MicroRNAs 34a and 223 Inhibits Lef1 Expression To Achieve Efficient Reprogramming into Macrophages

C/EBPa-Mediated Activation of MicroRNAs 34a and 223 Inhibits Lef1 Expression To Achieve Efficient Reprogramming into Macrophages

A lack of secretory leukocyte protease inhibitor (SLPI) causes defects in granulocytic differentiation

Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells

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