Receptor Tyrosine Kinases: Translocation Partners in Hematopoietic Disorders

RTK overactivation by chromosomal translocation and fusion protein formation can result in aberrant cell function and cancer progression. In hematological cancers, the order of domains in RTK fusion proteins displays the RTK-derived domain as the C-terminal fusion partner, fused to a variety of other proteins as the N-terminal fusion partner. This differs from RTK fusion proteins in solid tumors, which typically display the RTK as the N-terminal fusion partner. RTK translocations involving RET, CSF1R, and NTRK3 in patients present novel potential therapeutic targets. The use of tyrosine kinase inhibitors (TKIs) is increasingly effective in treating patients with hematological cancers driven by RTK fusion proteins. Although TKI clinical trials are prevalent, the use of TKIs often results in drug resistance. Cancer genome sequencing is becoming increasingly important in the determination of appropriate TKI administration for patients. Receptor tyrosine kinases (RTKs) activate various signaling pathways and regulate cellular proliferation, survival, migration, and angiogenesis. Malignant neoplasms often circumvent or subjugate these pathways by promoting RTK overactivation through mutation or chromosomal translocation. RTK translocations create a fusion protein containing a dimerizing partner fused to an RTK kinase domain, resulting in constitutive kinase domain activation, altered RTK cellular localization, upregulation of downstream signaling, and novel pathway activation. While RTK translocations in hematological malignancies are relatively rare, clinical evidence suggests that patients with these genetic abnormalities benefit from RTK-targeted inhibitors. Here, we present a timely review of an exciting field by examining RTK chromosomal translocations in hematological cancers, such as Anaplastic Lymphoma Kinase (ALK), Fibroblast Growth Factor Receptor (FGFR), Platelet-Derived Growth Factor Receptor (PDGFR), REarranged during Transfection (RET), Colony Stimulating Factor 1 Receptor (CSF1R), and Neurotrophic Tyrosine Kinase Receptor Type 3 (NTRK3) fusions, and discuss current therapeutic options. Receptor tyrosine kinases (RTKs) activate various signaling pathways and regulate cellular proliferation, survival, migration, and angiogenesis. Malignant neoplasms often circumvent or subjugate these pathways by promoting RTK overactivation through mutation or chromosomal translocation. RTK translocations create a fusion protein containing a dimerizing partner fused to an RTK kinase domain, resulting in constitutive kinase domain activation, altered RTK cellular localization, upregulation of downstream signaling, and novel pathway activation. While RTK translocations in hematological malignancies are relatively rare, clinical evidence suggests that patients with these genetic abnormalities benefit from RTK-targeted inhibitors. Here, we present a timely review of an exciting field by examining RTK chromosomal translocations in hematological cancers, such as Anaplastic Lymphoma Kinase (ALK), Fibroblast Growth Factor Receptor (FGFR), Platelet-Derived Growth Factor Receptor (PDGFR), REarranged during Transfection (RET), Colony Stimulating Factor 1 Receptor (CSF1R), and Neurotrophic Tyrosine Kinase Receptor Type 3 (NTRK3) fusions, and discuss current therapeutic options. a murine hematopoietic progenitor cell line dependent on the cytokine IL-3 for proliferation. a blood cancer containing the genetic translocation of the FGFR1 gene, location at position p11 of chromosome 8. cancer of myeloid cells, most often nonlymphocytic white blood cells, but sometimes red blood cells or megakaryocytes. a non-Hodgkin lymphoma considered to be a subtype of peripheral T cell lymphoma. a B cell lineage mixed phenotype acute leukemia (MPAL), resulting from the combination of two forms of leukemia. murine B cell hybridoma line dependent on the cytokine interleukin-6 (IL-6) for growth. a murine IL-3-dependent pro-B cell line frequently used as a model system for determining the oncogenicity of proteins. cancer resulting in an overproduction of eosinophils, a type of white blood cell. cancer of mature lymphocytes originating in the bone marrow. cancer of white blood cells frequently associated with the Philadelphia chromosomal translocation encoding BCR-ABL. cancer of B cells and the most common type of non-Hodgkin lymphoma. fluorescent probes that hybridize to specific chromosomal regions allowing their identification; used to determine genetic translocations. one of 58 RTKs belonging to the PDGFR superfamily. mutation in the ATP-binding pocket of an RTK,which reduces binding of inhibitors; results in inhibitor-resistant cancers, often arising after initial treatment with a TKI. one of 58 RTKs, belonging to the PDGFR receptor superfamily. cancer of blood-forming tissue; different types exist depending on the type of cancerous blood cell. cancer of lymphocytes, a type of white blood cell; separable into two main categories: Hodgkin disease and non-Hodgkin lymphoma (NHL). a cancer of plasma cells, which are antibody-producing white blood cells. new or abnormal tissue growth; malignant neoplasms are also referred to as cancer. a member of a family of growth factors that signal cell survival, growth, or differentiation. cell surface receptors with intrinsic tyrosine protein kinase activity; activated by growth factors, hormones, and cytokines (also see Boxes 1 and 2). cancer of immature lymphocytes in the bone marrow. rearrangement of nonhomologous chromosome parts resulting in the joining of two genes to create a gene fusion. bioactive small molecules that inhibit tyrosine kinase activity (see Table S1 in the supplemental information online). inhibitory domain in the juxtamembrane domain of PDGFR containing two conserved tryptophan residues.