Hhex induces promyelocyte self-renewal and cooperates with growth factor independence to cause myeloid leukemia in mice
- Author(s)
- Jackson, JT; Ng, AP; Shields, BJ; Haupt, S; Haupt, Y; McCormack, MP;
- Details
- Publication Year 2018-02-27,Volume 2,Issue #4,Page 347-360
- Journal Title
- Blood Advancers
- Publication Type
- Journal Article
- Abstract
- The hematopoietically expressed homeobox (Hhex) transcription factor is overexpressed in human myeloid leukemias. Conditional knockout models of murine acute myeloid leukemia indicate that Hhex maintains leukemia stem cell self-renewal by enabling Polycomb-mediated epigenetic repression of the Cdkn2a tumor suppressor locus, encoding p16(Ink4a) and p19(Arf) However, whether Hhex overexpression also affects hematopoietic differentiation is unknown. To study this, we retrovirally overexpressed Hhex in hematopoietic progenitors. This enabled serial replating of myeloid progenitors, leading to the rapid establishment of interleukin-3 (IL-3)-dependent promyelocytic cell lines. Use of a Hhex-ERT2 fusion protein demonstrated that continuous nuclear Hhex is required for transformation, and structure function analysis demonstrated a requirement of the DNA-binding and N-terminal-repressive domains of Hhex for promyelocytic transformation. This included the N-terminal promyelocytic leukemia protein (Pml) interaction domain, although deletion of Pml failed to prevent Hhex-induced promyelocyte transformation, implying other critical partners. Furthermore, deletion of p16(Ink4a) or p19(Arf) did not promote promyelocyte transformation, indicating that repression of distinct Hhex target genes is required for this process. Indeed, transcriptome analysis showed that Hhex overexpression resulted in repression of several myeloid developmental genes. To test the potential for Hhex overexpression to contribute to leukemic transformation, Hhex-transformed promyelocyte lines were rendered growth factor-independent using a constitutively active IL-3 receptor common beta subunit (betacV449E). The resultant cell lines resulted in a rapid promyelocytic leukemia in vivo. Thus, Hhex overexpression can contribute to myeloid leukemia via multiple mechanisms including differentiation blockade and enabling epigenetic repression of the Cdkn2a locus.
- Publisher
- ASH
- Research Division(s)
- Cancer And Haematology
- PubMed ID
- 29453249
- Publisher's Version
- https://doi.org/10.1182/bloodadvances.2017013243
- Open Access at Publisher's Site
https://doi.org/10.1182/bloodadvances.2017013243- NHMRC Grants
- NHMRC/1003391, NHMRC/1126772,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-02-28 10:12:05
Last Modified: 2018-02-28 11:18:06