7. Hematopoietic master regulators and leukemic stem cell evolution.

Staff: Edo Vellenga, Jan Jacob Schuringa,

PI : Hein Schepers

MD-PhD: Gerbirg Berger

PhD: Katharina Mattes

Technician: Marjan Rozenveld Geugien

Normal hematopoietic stem cells self-renew and differentiate into all different blood lineages. Precise regulation of the hematopoietic stem cell pool by transcriptional master regulators is critical, since dysregulation can lead to leukemogenesis. Acute myeloid leukemia (AML) accounts for 25% of all leukemias. Although c urrent therapies are very effective in reducing leukemic cell load, the majority of patients still relapse . This indicates that not all leukemic cells are eradicated and that some cells, known as leukemic stem cells (LSCs), must persist in the bone marrow.

LSCs have similar or enhanced self-renewal abilities, but have lost the ability to differentiate into the appropriate hematopoietic lineages. The expression of many master regulators (such as: STAT5, CEBPα, PU.1, CITED2) is changed in these LSCs, which suggest that they have a role in leukemic transformation.

A number of genetic lesions in human AML, such as RUNX1-ETO, PML-RAR and FLT3-ITD have been implicated in leukemogenisis and are known to reduce or inactivate expression of the myeloid transcription factor PU.1 . Mouse models have shown that reduced expression of PU.1 leads to AML development , indicating that PU.1 is an important tumor suppressor. However, the mechanisms involved remain unclear. Our data indicates that PU.1 represses th e transcriptional coactivator CBP/p300-interacting-transactivator-with-an ED-rich-tail 2 (CITED2).

We have shown before that CITED2 is essential for adult HSC maintenance. CITED2 deletion in adult HSCs leads to rapid animal lethality, resulting from hematopoietic stem and progenitor cell (HSPC)-specific apoptosis. CITED2 has furthermore been shown to modulate cisplatinum resistance of cervical carcinoma cells. The fact that CITED2 expression is essential for HSC maintenance and functions as a cofactor in oncogene-induced transformation suggests that CITED2 could also play a role in leukemia initiation or leukemic stem cell maintenance.

As increased CITED2 expression results in HSC maintenance and decreased PU.1 leads to a block in myeloid differentiation, these two master regulators may act in concert and likely contribute to leukemic development. In order to gain more insight into the biology of the LSC, it is important to model both in vitro as well as in in vivo xenograft mouse models how such master regulators co-ordinately affect different phases of leukemia development .

By understanding such processes on a molecular level we can develop more effective treatments in order to eradicate leukemia.

Selected references

Schepers H, Wierenga AT, Vellenga E et al. STAT5-mediated self-renewal of normal hematopoietic and leukemic stem cells. JAK-STAT. 2012; 1:1-10.

Kranc KR, Schepers H, Rodrigues NP et al. Cited2 is an essential regulator of adult hematopoietic stem cells. Cell Stem Cell. 2009; 5: 659-665

Sc hepers H , van Gosliga D, Wierenga AT et al. STAT5 is required for long-term maintenance of normal and leukemic human stem/progenitor cells. Blood . 2007; 110: 2880-2888.

Schepers H , Wierenga AT, van Gosliga D et al. Re-introduction of C/EBPα in leukemic CD34+ stem/progenitor cells impairs self-renewal and partially restores myelopoiesis. Blood. 2007; 110: 1317-1325.

Wierenga AT, Schepers H, Moore et al. STAT5-induced self-renewal and impaired myelopoiesis of human hematopoietic stem/progenitor cells involves down-modulation of C/EBP a . Blood. 2006; 107: 4326-4333.

For more information on this project, please contact Hein Schepers