Contributions
Abstract: EP752
Type: E-Poster Presentation
Session title: Hematopoiesis, stem cells and microenvironment
Background
Leukemic stem cells (LSCs) share characteristics of hematopoietic stem cells (HSCs) and represent the major therapeutic hurdle in leukemia patients. Many leukemic entities depend on an activated JAK/STAT signaling pathway, with STAT5 being critical in hematopoiesis and leukemia. As specific STAT5 inhibitors have not entered the clinics yet, alternative drug targets are needed. STAT5 is actually two distinct transcription factors, STAT5A and STAT5B which share more than 96% protein identity. It is widely believed that STAT5A and STAT5B are functionally redundant in the hematopoietic system. This dogma is challenged by the recent finding that activating STAT5 mutations in leukemia are restricted to STAT5B.
Aims
We aimed at understanding the distinct and individual roles of STAT5A and STAT5B in HSC and LSC self-renewal to identify downstream druggable targets.
Methods
We characterized the HSC compartment of mice lacking STAT5A or STAT5B via flow cytometry, single cell RNA-Seq and in vitro assays. We analysed Stat5a-/- or Stat5b-/- HSC and LSC potency in in vivo settings including serial transplantation and 5-FU treatment. We validated the potential downstream target CD9 in primary STAT5-dependent leukemia patient samples.
Results
We identified distinct functions for STAT5A and STAT5B in HSCs and in LSCs and define STAT5B as the driving force behind the maintenance and self-renewal of these cell types. We identify CD9 as a novel STAT5B target gene and show that the levels of CD9 correlate positively with STAT5 phosphorylation and negatively with the survival of STAT5-dependent leukemia patients. The elevated CD9 surface levels on LSCs render the cells particularly sensitive towards CD9-blocking, which we show to induce differentiation and apoptosis.
Conclusion
We suggest that CD9 may serve in prognosis and therapy of STAT5-dependent leukemia. We show that it is vital to consider STAT5A and STAT5B as distinct entities in normal and malignant hematopoiesis.
Keyword(s): HSC, Self-renewal, STAT5
Abstract: EP752
Type: E-Poster Presentation
Session title: Hematopoiesis, stem cells and microenvironment
Background
Leukemic stem cells (LSCs) share characteristics of hematopoietic stem cells (HSCs) and represent the major therapeutic hurdle in leukemia patients. Many leukemic entities depend on an activated JAK/STAT signaling pathway, with STAT5 being critical in hematopoiesis and leukemia. As specific STAT5 inhibitors have not entered the clinics yet, alternative drug targets are needed. STAT5 is actually two distinct transcription factors, STAT5A and STAT5B which share more than 96% protein identity. It is widely believed that STAT5A and STAT5B are functionally redundant in the hematopoietic system. This dogma is challenged by the recent finding that activating STAT5 mutations in leukemia are restricted to STAT5B.
Aims
We aimed at understanding the distinct and individual roles of STAT5A and STAT5B in HSC and LSC self-renewal to identify downstream druggable targets.
Methods
We characterized the HSC compartment of mice lacking STAT5A or STAT5B via flow cytometry, single cell RNA-Seq and in vitro assays. We analysed Stat5a-/- or Stat5b-/- HSC and LSC potency in in vivo settings including serial transplantation and 5-FU treatment. We validated the potential downstream target CD9 in primary STAT5-dependent leukemia patient samples.
Results
We identified distinct functions for STAT5A and STAT5B in HSCs and in LSCs and define STAT5B as the driving force behind the maintenance and self-renewal of these cell types. We identify CD9 as a novel STAT5B target gene and show that the levels of CD9 correlate positively with STAT5 phosphorylation and negatively with the survival of STAT5-dependent leukemia patients. The elevated CD9 surface levels on LSCs render the cells particularly sensitive towards CD9-blocking, which we show to induce differentiation and apoptosis.
Conclusion
We suggest that CD9 may serve in prognosis and therapy of STAT5-dependent leukemia. We show that it is vital to consider STAT5A and STAT5B as distinct entities in normal and malignant hematopoiesis.
Keyword(s): HSC, Self-renewal, STAT5