The Homeobox Transcription Factor HB9 Induces Senescence and Blocks Differentiation in Hematopoietic Stem and Progenitor Cells

Overview

Journal Haematologica

Specialty Hematology

Date 2018 Aug 11

PMID 30093397

Citations 13

Authors

Deborah Ingenhag

Sven Reister

Franziska Auer

Sanil Bhatia

Sarah Wildenhain

Daniel Picard

Marc Remke

Jessica I Hoell

Andreas Kloetgen

Dennis Sohn

Reiner U Janicke

Gesine Koegler

Arndt Borkhardt

Julia Hauer

Affiliations

Soon will be listed here.

Abstract

The homeobox gene encodes for the transcription factor HB9, which is essential for pancreatic as well as motor neuronal development. Beside its physiological expression pattern, aberrant HB9 expression has been observed in several neoplasias. Especially in infant translocation t(7;12) acute myeloid leukemia, aberrant HB9 expression is the only known molecular hallmark and is assumed to be a key factor in leukemic transformation. However, so far, only poor functional data exist addressing the oncogenic potential of HB9 or its influence on hematopoiesis. We investigated the influence of HB9 on cell proliferation and cell cycle , as well as on hematopoietic stem cell differentiation using murine and human model systems. , HB9 expression led to premature senescence in human HT1080 and murine NIH3T3 cells, providing for the first time evidence for an oncogenic potential of HB9. Onset of senescence was characterized by induction of the p53-p21 tumor suppressor network, resulting in growth arrest, accompanied by morphological transformation and expression of senescence-associated β-galactosidase. , HB9-transduced primary murine hematopoietic stem and progenitor cells underwent a profound differentiation arrest and accumulated at the megakaryocyte/erythrocyte progenitor stage. In line, gene expression analyses revealed expression of erythropoiesis-related genes in human CD34hematopoietic stem and progenitor cells upon HB9 expression. In summary, the novel findings of HB9-dependent premature senescence and myeloid-biased perturbed hematopoietic differentiation, for the first time shed light on the oncogenic properties of HB9 in translocation t(7;12) acute myeloid leukemia.

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