PUBLICATION
LMO2 activation by deacetylation is indispensable for hematopoiesis and T-ALL leukemogenesis
- Authors
- Morishima, T., Krahl, A.C., Nasri, M., Xu, Y., Aghaallaei, N., Findik, B., Klimiankou, M., Ritter, M., Hartmann, M.D., Gloeckner, C.J., Stefańczyk, S., Lindner, C., Oswald, B., Bernhard, R., Hähnel, K., Hermanutz-Klein, U., Ebinger, M., Handgretinger, R., Casadei, N., Welte, K., Andre, M., Müller, P., Bajoghli, B., Skokowa, J.
- ID
- ZDB-PUB-190802-2
- Date
- 2019
- Source
- Blood 134(14): 1159-1175 (Journal)
- Registered Authors
- Aghaallaei, Narges, Bajoghli, Baubak, Müller, Patrick
- Keywords
- none
- MeSH Terms
-
- Acetylation
- Adaptor Proteins, Signal Transducing/metabolism*
- Animals
- Cells, Cultured
- HEK293 Cells
- Hematopoiesis*
- Humans
- LIM Domain Proteins/metabolism*
- Leukopoiesis
- Mice
- Models, Molecular
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism*
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
- Proto-Oncogene Proteins/metabolism*
- Transcription Factors/metabolism*
- Zebrafish
- Zebrafish Proteins/metabolism*
- PubMed
- 31366618 Full text @ Blood
Citation
Morishima, T., Krahl, A.C., Nasri, M., Xu, Y., Aghaallaei, N., Findik, B., Klimiankou, M., Ritter, M., Hartmann, M.D., Gloeckner, C.J., Stefańczyk, S., Lindner, C., Oswald, B., Bernhard, R., Hähnel, K., Hermanutz-Klein, U., Ebinger, M., Handgretinger, R., Casadei, N., Welte, K., Andre, M., Müller, P., Bajoghli, B., Skokowa, J. (2019) LMO2 activation by deacetylation is indispensable for hematopoiesis and T-ALL leukemogenesis. Blood. 134(14):1159-1175.
Abstract
LMO2 (hematopoietic transcription factor LIM domain only 2), a member of the TAL1 transcriptional complex, plays an essential role during early hematopoiesis and is frequently activated in T cell acute lymphoblastic leukemia (T-ALL) patients. Here, we demonstrated that LMO2 is activated by deacetylation on lysine 74 and 78 via the nicotinamide phosphoribosyltransferase (NAMPT)/sirtuin 2 (SIRT2) pathway. LMO2 deacetylation enables LMO2 to interact with LDB1 and activate the TAL1 complex. NAMPT/SIRT2-mediated activation of LMO2 by deacetylation is essential for hematopoietic differentiation of induced pluripotent stem (iPS) cells and blood formation in zebrafish embryos. In T-ALL, deacetylated LMO2 induces expression of TAL1 complex target genes HHEX, NKX3.1 as well as LMO2 autoregulation. Consistent with this, inhibition of NAMPT or SIRT2 suppressed the in vitro growth and in vivo engraftment of T-ALL cells via diminished LMO2 deacetylation. This new molecular mechanism may provide new therapeutic possibilities in T-ALL and may contribute to the development of new methods for in vitro generation of blood cells.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping