NAMPT-mediated LMO2 deacetylation is indispensable for hematopoiesis and T-ALL leukemogenesis

T Morishima; AC Krahl; Y Xu; N Aghaallaei; M Nasri; B Findik; B Bajoghli; P Müller; K Welte; J Skokowa

doi:10.1055/s-0039-1687171

Klinische Pädiatrie, Table of Contents

Klin Padiatr 2019; 231(03): 168
DOI: 10.1055/s-0039-1687171

Abstracts

Georg Thieme Verlag KG Stuttgart · New York

NAMPT-mediated LMO2 deacetylation is indispensable for hematopoiesis and T-ALL leukemogenesis

Authors

T Morishima

¹Department of Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Germany
AC Krahl

¹Department of Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Germany
Y Xu

¹Department of Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Germany
N Aghaallaei

¹Department of Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Germany
M Nasri

¹Department of Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Germany
B Findik

¹Department of Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Germany
B Bajoghli

¹Department of Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Germany
P Müller

²Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany
K Welte

³University Children's Hospital Tübingen, Germany
J Skokowa

¹Department of Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Germany

Abstract

Full Text

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 deacetylation of LMO2 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.