LMO2 activation by deacetylation is indispensable for hematopoiesis and T-ALL leukemogenesis

Morishima, Tatsuya; Krahl, Ann-Christin; Nasri, Masoud; Xu, Yitong; Aghaallaei, Narges; Findik, Betül; Klimiankou, Maksim; Ritter, Malte; Hartmann, M.D.; Gloeckner, Christian Johannes; Stefanczyk, Sylwia; Lindner, Christian; Oswald, Benedikt; Bernhard, Regine; Hähnel, Karin; Hermanutz-Klein, Ursula; Ebinger, Martin; Handgretinger, Rupert; Casadei, Nicolas; Welte, Karl; André, Maya C.; Müller, Patrick; Bajoghli, Baubak; Skokowa, Julia

doi:10.1182/blood.2019000095

Cited by 26 publications

(38 citation statements)

References 93 publications

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“…We recently demonstrated that NAMPT and SIRT2 are essential for early blood cell formation 17 . The results of the present study complemented these findings.…”

Section: Discussionmentioning

confidence: 99%

“…Identification of specific selective inhibitors of NAMPT and SIRT2 15,16 has made it possible to evaluate the specific roles of each of these factors in different physiological and pathological processes. We recently identified important roles of NAMPT and SIRT2 during early stages of hematopoietic differentiation of iPS cells using a feeder-free, serum-free monolayer-based differentiation protocol 17 . However, we did not study granulocytic differentiation of iPS cells using this method.…”

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confidence: 99%

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NAMPT/SIRT2–mediated inhibition of the p53-p21 signaling pathway is indispensable for maintenance and hematopoietic differentiation of human iPS cells

Xu¹,

Nasri²,

Dannenmann

et al. 2020

Preprint

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Background: Nicotinamide phosphoribosyltransferase (NAMPT) regulates cellular functions through the protein deacetylation activity of nicotinamide adenine dinucleotide (NAD+)-dependent sirtuins (SIRTs). SIRTs regulate functions of histones and none-histone proteins. The role of NAMPT/SIRTs pathway in the regulation of maintenance and differentiation of human induced pluripotent stem (iPS) cells is not fully elucidated. Methods: We evaluated the effects of specific inhibitors of NAMPT-, or SIRT2 on the pluripotency, proliferation, survival and hematopoietic differentiation of human iPS cells. We also studied the molecular mechanism downstream of NAMPT/SIRTs in iPS cells. Results: We demonstrated that NAMPT is indispensable for the maintenance, survival and hematopoietic differentiation of induced pluripotent stem (iPS) cells. We found that inhibition of NAMPT or SIRT2 in iPS cells induces p53 protein by promoting its lysine acetylation. This leads to activation of the p53 target, p21, with subsequent cell cycle arrest and induction of apoptosis in iPS cells. NAMPT and SIRT2 inhibition also affects hematopoietic differentiation of iPS cells in an embryoid body (EB)-based cell culture system. Conclusions: Our data demonstrate the essential role of the NAMPT/SIRT2/p53/p21 signaling axis in the maintenance and hematopoietic differentiation of iPS cells.

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“…We recently demonstrated that NAMPT and SIRT2 are essential for early blood cell formation 17 . The results of the present study complemented these findings.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

NAMPT/SIRT2–mediated inhibition of the p53-p21 signaling pathway is indispensable for maintenance and hematopoietic differentiation of human iPS cells

Xu¹,

Nasri²,

Dannenmann

et al. 2020

Preprint

Self Cite

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“…It would be interesting to investigate whether NAMPT-triggered protein deacetylation governs the development of tissues and organs of mesoderm, endoderm or ectoderm origin, and whether SIRT2 or other SIRTs are involved. We recently demonstrated that NAMPT and SIRT2 are essential for early blood cell formation 17 . The results of the present study complemented these ndings.…”

Section: Discussionmentioning

confidence: 99%

“…A search for downstream targets of NAMPT/SIRT2 revealed that p53 is deacetylated by NAMPT/SIRT2 in iPS cells, leading to rapid and robust activation of p21 with subsequent cell cycle arrest and apoptosis of iPS cells. We recently reported that NAMPT deacetylates p53 in myeloid leukemia cells 17 . Our ndings in iPS cells further con rm the important role of NAMPT/SIRT2 in p53 deactivation through lysine deacetylation.…”

Section: Discussionmentioning

confidence: 99%

“…Identi cation of speci c selective inhibitors of NAMPT and SIRT2 15,16 has made it possible to evaluate the speci c roles of each of these factors in different physiological and pathological processes. We recently identi ed important roles of NAMPT and SIRT2 during early stages of hematopoietic differentiation of iPS cells using a feeder-free, serum-free monolayer-based differentiation protocol 17 . However, we did not study the granulocytic differentiation of iPS cells using this method.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

NAMPT/SIRT2–mediated inhibition of the p53-p21 signaling pathway is indispensable for maintenance and hematopoietic differentiation of human iPS cells

Xu¹,

Nasri²,

Dannenmann

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Nicotinamide phosphoribosyltransferase (NAMPT) regulates cellular functions through the protein deacetylation activity of nicotinamide adenine dinucleotide (NAD+)-dependent sirtuins (SIRTs). SIRTs regulate functions of histones and none-histone proteins. The role of NAMPT/SIRTs pathway in the regulation of maintenance and differentiation of human induced pluripotent stem (iPS) cells is not fully elucidated.Methods: We evaluated the effects of specific inhibitors of NAMPT-, or SIRT2 on the pluripotency, proliferation, survival and hematopoietic differentiation of human iPS cells. We also studied the molecular mechanism downstream of NAMPT/SIRTs in iPS cells.Results: We demonstrated that NAMPT is indispensable for the maintenance, survival and hematopoietic differentiation of induced pluripotent stem (iPS) cells. We found that inhibition of NAMPT or SIRT2 in iPS cells induces p53 protein by promoting its lysine acetylation. This leads to activation of the p53 target, p21, with subsequent cell cycle arrest and induction of apoptosis in iPS cells. NAMPT and SIRT2 inhibition also affect hematopoietic differentiation of iPS cells in an embryoid body (EB)-based cell culture system.Conclusions: Our data demonstrate the essential role of the NAMPT/SIRT2/p53/p21 signaling axis in the maintenance and hematopoietic differentiation of iPS cells.

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DNA methylation as a new tool for the differential diagnosis between T‐LBL and lymphocyte‐rich thymoma

Latiri,

Belhocine,

Smith

et al. 2024

The Journal of Pathology

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T‐lymphoblastic lymphoma (T‐LBL) and thymoma are two rare primary tumors of the thymus deriving either from T‐cell precursors or from thymic epithelial cells, respectively. Some thymoma subtypes (AB, B1, and B2) display numerous reactive terminal deoxynucleotidyl transferase‐positive (TdT+) T‐cell precursors masking epithelial tumor cells. Therefore, the differential diagnosis between T‐LBL and TdT+ T‐lymphocyte‐rich thymoma could be challenging, especially in the case of needle biopsy. To distinguish between T‐LBL and thymoma‐associated lymphoid proliferations, we analyzed the global DNA methylation using two different technologies, namely MeDIP array and EPIC array, in independent samples series [17 T‐LBLs compared with one TdT+ lymphocyte‐rich thymoma (B1 subtype) and three normal thymi, and seven lymphocyte‐rich thymomas compared with 24 T‐LBLs, respectively]. In unsupervised principal component analysis (PCA), T‐LBL and thymoma samples clustered separately. We identified differentially methylated regions (DMRs) using MeDIP‐array and EPIC‐array datasets and nine overlapping genes between the two datasets considering the top 100 DMRs including ZIC1, TSHZ2, CDC42BPB, RBM24, C10orf53, and MACROD2. In order to explore the DNA methylation profiles in larger series, we defined a classifier based on these six differentially methylated gene promoters, developed an MS‐MLPA assay, and demonstrated a significant differential methylation between thymomas (hypomethylated; n = 48) and T‐LBLs (hypermethylated; n = 54) (methylation ratio median 0.03 versus 0.66, respectively; p < 0.0001), with MACROD2 methylation status the most discriminating. Using a machine learning strategy, we built a prediction model trained with the EPIC‐array dataset and defined a cumulative score taking into account the weight of each feature. A score above or equal to 0.4 was predictive of T‐LBL and conversely. Applied to the MS‐MLPA dataset, this prediction model accurately predicted diagnoses of T‐LBL and thymoma. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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LMO2 activation by deacetylation is indispensable for hematopoiesis and T-ALL leukemogenesis

Abstract: Key Points LMO2 is deacetylated by the NAMPT/SIRT2 pathway. LMO2 deacetylation is essential for LIM domain binding 1 binding and TAL1 complex activation during hematopoiesis and T-ALL leukemogenesis.

Cited by 26 publications

References 93 publications

NAMPT/SIRT2–mediated inhibition of the p53-p21 signaling pathway is indispensable for maintenance and hematopoietic differentiation of human iPS cells

NAMPT/SIRT2–mediated inhibition of the p53-p21 signaling pathway is indispensable for maintenance and hematopoietic differentiation of human iPS cells

NAMPT/SIRT2–mediated inhibition of the p53-p21 signaling pathway is indispensable for maintenance and hematopoietic differentiation of human iPS cells

DNA methylation as a new tool for the differential diagnosis between T‐LBL and lymphocyte‐rich thymoma

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