Abstract
Both normal as well leukemic hematopoietic stem cells critically depend on their microenvironment in the bone marrow for processes such as self-renewal, survival and differentiation, although the exact pathways that are involved remain poorly understood. We performed transcriptome analysis on primitive CD34+ acute myeloid leukemia (AML) cells (n = 46), their more differentiated CD34− leukemic progeny, and normal CD34+ bone marrow cells (n = 31) and focused on differentially expressed genes involved in adhesion and migration. Thus, Engulfment and Motility protein 1 (ELMO1) was identified amongst the top 50 most differentially expressed genes. ELMO1 is a crucial link in the signaling cascade that leads to activation of RAC GTPases and cytoskeleton rearrangements. We confirmed increased ELMO1 expression at the mRNA and protein level in a panel of AML samples and showed that high ELMO1 expression is an independent negative prognostic factor in normal karyotype (NK) AML in three large independent patient cohorts. Downmodulation of ELMO1 in human CB CD34+ cells did not significantly alter expansion, progenitor frequency or differentiation in stromal co-cultures, but did result in a decreased frequency of stem cells in LTC-IC assays. In BCR-ABL-transduced human CB CD34+ cells depletion of ELMO1 resulted in a mild decrease in proliferation, but replating capacity of progenitors was severely impaired. Downregulation of ELMO1 in a panel of primary CD34+ AML cells also resulted in reduced long-term growth in stromal co-cultures in two out of three cases. Pharmacological inhibition of the ELMO1 downstream target RAC resulted in a severely impaired proliferation and survival of leukemic cells. Finally, ELMO1 depletion caused a marked decrease in SDF1-induced chemotaxis of leukemic cells. Taken together, these data show that inhibiting the ELMO1-RAC axis might be an alternative way to target leukemic cells.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous disease in which various molecular events lead to a block in differentiation along the myeloid lineage, resulting in an accumulation of immature cells termed leukemic blasts, as well as impaired normal hematopoiesis
Engulfment and Motility protein 1 (ELMO1) is a crucial link in the signaling cascade that leads to activation of RAC GTPases and cytoskeleton rearrangements and we decided to study its role in more detail
Increased expression of ELMO1 was further confirmed by independent Q-PCRs, which showed a good correlation with the Illumina BeadArrays data was paralleled by increased protein levels in two representative cases. (H) High expression of ELMO1 predicts poor survival in a cohort of normal karyotype (NK) AML
Summary
Acute myeloid leukemia (AML) is a heterogeneous disease in which various molecular events lead to a block in differentiation along the myeloid lineage, resulting in an accumulation of immature cells termed leukemic blasts, as well as impaired normal hematopoiesis. Several gene expression profiling (GEP) studies have been performed in order to identify leukemia-specific gene expression patterns and select a gene, or more likely a panel of genes, that could be used to better classify patients within the existing subgroups [3,4,5,6,7,8]. Most of these studies were performed on the total mononuclear fraction (MNC) of AML samples, which contains mostly leukemic blasts. Knockdown of ELMO1 or inhibition one of its downstream protein RAC impaired long-term expansion of leukemic cells on stroma, and ELMO1 depletion decreased the migration potential of hematopoietic cells towards an SDF-1 gradient
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