GRIK5 DRIVES SELF RENEWAL PATHWAYS IN HUMAN ACUTE MYELOID LEUKEMIA CELLS
Author(s): ,
Jianglong Xia
Affiliations:
Department of Medicine V, Hematology, Oncology and Rheumatology,University Hospital Heidelberg, Heidelberg, Germany,Heidelberg,Germany;Molecular Medicine Partnership Unit (MMPU),University of Heidelberg and European Molecular Biology Laboratory (EMBL),Heidelberg,Germany
,
Swati Garg
Affiliations:
Department of Medicine V, Hematology, Oncology and Rheumatology,University Hospital Heidelberg, Heidelberg, Germany,Heidelberg,Germany;Molecular Medicine Partnership Unit (MMPU),University of Heidelberg and European Molecular Biology Laboratory (EMBL),Heidelberg,Germany
,
Lixiazi He
Affiliations:
Department of Medicine V, Hematology, Oncology and Rheumatology,University Hospital Heidelberg, Heidelberg, Germany,Heidelberg,Germany;Molecular Medicine Partnership Unit (MMPU),University of Heidelberg and European Molecular Biology Laboratory (EMBL),Heidelberg,Germany
,
Prarabdha Jagdhane
Affiliations:
Department of Medicine V, Hematology, Oncology and Rheumatology,University Hospital Heidelberg, Heidelberg, Germany,Heidelberg,Germany;Molecular Medicine Partnership Unit (MMPU),University of Heidelberg and European Molecular Biology Laboratory (EMBL),Heidelberg,Germany
,
Müller-Tidow Carsten
Affiliations:
Department of Medicine V, Hematology, Oncology and Rheumatology,University Hospital Heidelberg, Heidelberg, Germany,Heidelberg,Germany;Molecular Medicine Partnership Unit (MMPU),University of Heidelberg and European Molecular Biology Laboratory (EMBL),Heidelberg,Germany
Pabst Caroline
Affiliations:
Department of Medicine V, Hematology, Oncology and Rheumatology,University Hospital Heidelberg, Heidelberg, Germany,Heidelberg,Germany;Molecular Medicine Partnership Unit (MMPU),University of Heidelberg and European Molecular Biology Laboratory (EMBL),Heidelberg,Germany
EHA Library. Xia J. Jun 15, 2019; 267281; PS980
Jianglong Xia
Jianglong Xia
Contributions
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Abstract

Abstract: PS980

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background

Acute myeloid leukemia (AML) is characterized by a block in differentiation and uncontrolled proliferation of immature hematopoietic precursor cells. Self-renewing leukemia stem cells (LSCs) are supposed to initiate and promote the disease. In our previous study, we had identified a set of genes associated with high LSC frequency in normal karyotype AML. Among these, we identified the Glutamate receptor ionotropic, kainate 5 (GRIK5) coding for a transmembrane protein, which is known to be expressed in the central nervous system as a ligand-gated ion channel receptor.

Aims

In this study, we aimed to understand the functional role of GRIK5 in normal HSPCs and AML cells. In particular, we investigated how GRIK5 drives self-renewal pathways in AML and whether GRIK5 might represent a novel cell surface target for anti-leukemic therapy.

Methods

We performed knockdown (KD) experiments using small hairpin (sh) RNAs to determine whether GRIK5 was essential for proliferation, differentiation, and survival of primary human cord blood CD34+ HSPCs, leukemic cell lines, and primary human-derived AML xenograft cells. Furthermore, lentivirally transduced HSPCs and leukemia cells were analyzed in vitro for proliferative output, viability, immunophenotype, and colony formation potential. RNA sequencing (RNA-Seq) and whole cell mass spectrometry followed by enrichment analysis were used to identify key signaling pathways affected by GRIK5 KD.

Results

We found that knockdown of GRIK5 expression strongly impaired leukemic cell proliferation and totally abrogated human leukemic engraftment in immunocompromised mice. In the healthy system, however, GRIK5 KD predominantly reduced the proliferative output of more committed progenitors, while more immature HSPCs were less affected. RNA-Seq data points towards a major involvement in several key self-renewal pathways.

Conclusion

Here we found that the surface receptor GRIK5 is overexpressed in the majority of AML samples compared to healthy HSPCs. GRIK5 plays a pivotal role in proliferation, differentiation, and engraftment capacity of primary human leukemia cells in xenotransplantation assays and might, therefore, be used as a novel therapeutic target for anti-leukemic therapies.

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): AML, Leukemic stem cell

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