Preponderant genomic sequencing and clinical evidence have revealed the remarkable heterogeneity that underpins leukemia. Such efforts have brought to the forefront new oncogenic alterations and mechanisms of drug resistance. This dissertation is focused on the identification and characterization of intrinsic and extrinsic mechanisms of receptor tyrosine kinase (RTK) activation in the setting of leukemia. An understanding of these mechanisms can be harnessed clinically to facilitate the development of new therapies and, thereby expand the promise of precision medicine. This work implicates that disrupting the crosstalk between leukemia cells and the marrow microenvironment could circumvent drug resistance and improve patient outcomes.