From the outside, from within: Biological and therapeutic relevance of signal transduction in T-cell acute lymphoblastic leukemia

•We review the knowledge on external stimuli activating pro-tumoral signaling pathways involved in T-cell leukemia.•We also address cell-intrinsic lesions activating the same signaling pathways•We discuss the potential of signaling players as therapeutic targets in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that arises from clonal expansion of transformed T-cell precursors. In this review we summarize the current knowledge on the external stimuli and cell-intrinsic lesions that drive aberrant activation of pivotal, pro-tumoral intracellular signaling pathways in T-cell precursors, driving transformation, leukemia expansion, spread or resistance to therapy. In addition to their pathophysiological relevance, receptors and kinases involved in signal transduction are often attractive candidates for targeted drug development. As such, we discuss also the potential of T-ALL signaling players as targets for therapeutic intervention.