Growth receptor bound protein-2 (GRB2) expands myeloid cells and increases proliferation in chronic myeloid leukemia (CML)

Growth receptor bound protein-2 (GRB2) is an intracellular adapter protein responsible for linking receptor tyrosine kinases to downstream signaling proteins involved in cellular growth and differentiation. GRB2 is overexpressed in certain forms of human cancer, but no research has investigated GRB2 overexpression in chronic myeloid leukemia (CML), a disease involving the over-proliferation of myeloid cells. GRB2 is upstream of several cellular signaling pathways involved in the tyrosine kinase (TK) breakpoint cluster region-Abelson murine leukemia viral oncogene-1 (BCR-ABL). BCRABL is the transforming factor in 95% of CML cases. Here we demonstrate that GRB2 is overexpressed in the human CML cell line K562. Furthermore, we demonstrate that GRB2 overexpression increases proliferation of K562 cells. Additionally, we show that in vivo overexpression of GRB2 in zebrafish (Danio rerio) causes a 2-fold expansion of myeloid cells relative to mock-injected fish at 24 hours post fertilization (hpf). Finally, we demonstrate that targeted antagonism of GRB2’s SH2 binding region blocks proliferation of K562 cells. Our findings demonstrate the role of GRB2 overexpression in the proliferation of both normal and malignant myeloid cells. These findings highlight GRB2 overexpression as a potential biomarker for disease prevention, treatment optimization, and a target for new drug therapies to treat CML.