A novel role for the EMT regulator, snai1, in hematopoiesis and leukemia

Catherine Carmichael, Steven Goossens, Benjamin Kile, Jody J Haigh

Research output: Contribution to conferencePoster

Abstract

While the epithelial to mesenchyme transition (EMT) is integral for development of many solid organs and tissues, EMT regulators are now emerging as key players in development of the more fluid hematopoietic system. The mechanisms involved, however, remain to be elucidated. Snai1 is a key EMT regulator that is highly expressed in human AML compared to normal CD34+ cells, and whose overexpression induces myeloid leukemia in mice. Its role during hematopoietic development, however, remains unclear. Using both retroviral and transgenic overexpression systems we have found that increased levels of Snai1 during hematopoiesis induces hematopoietic stem, progenitor and mature myeloid cell defects. Hematopoietic restricted expression of a Snai1 transgene results in lethality at E17.5-E18.5. Embryos are anemic, with normal primitive hematopoiesis but impaired definitive erythropoiesis and megakaryopoiesis. Retroviral overexpression of Snai1 (MSCV-Snai1-IRES-GFP) in adult murine hematopoietic stem and progenitor cells results in a 10-fold increase in the proportion of GFP+ Lin-Sca1+Kit+ (LSK) cells in the bone marrow, which is driven by an expansion of short term repopulating HSCs (ST-HSCs; LSK Flt3-, CD34+). These ST-HSCs, however, are functionally impaired as demonstrated by a lack of CFU-S forming potential. The myeloid progenitor compartment is also abnormal, with a significantly increased proportion of GFP+ GMPs and decreased proportion of GFP+ CMPs and MEPs resulting in a bias towards macrophage/granulocyte production and concomitant reduction in erythroid and megakaryocytic lineages.

This Snai1 overexpression phenotype is reminiscent of the combined phenotypes observed in the individual Gfi1 and Gfi1b knockout mice, suggesting a possible mechanism involving competition/alteration of their common co-factor, the chromatin modulator Lsd1. To further delineate the mechanisms by which Snai1 overexpression perturbs hematopoiesis we are performing ChIP-seq and RNA-seq experiments to investigate changes in gene expression, Lsd1 binding and function and Gfi1/1b transcriptional activity.
Original languageEnglish
PagesS56
Number of pages1
DOIs
Publication statusPublished - 2015
EventISEH 44th Annual Scientific Meeting: International Society for Experimental Hematology - Kyoto International Conference Center, Kyoto, Japan
Duration: 17 Sep 201519 Sep 2015
Conference number: 44
http://www.iseh.org/events/EventDetails.aspx?id=503256

Conference

ConferenceISEH 44th Annual Scientific Meeting
Abbreviated title44th Annual Scientific Meeting of the ISEH
CountryJapan
CityKyoto
Period17/09/1519/09/15
Internet address

Cite this

Carmichael, C., Goossens, S., Kile, B., & Haigh, J. J. (2015). A novel role for the EMT regulator, snai1, in hematopoiesis and leukemia. S56. Poster session presented at ISEH 44th Annual Scientific Meeting, Kyoto, Japan. https://doi.org/10.1016/j.exphem.2015.06.094