Cytokine receptor splice variants in hematologic diseases

Cytokine and cytokine receptors are important regulators of hematopoiesis. Hematopoietic stem cells (HSCs) and progenitors differentiate into the myeloid or lymphoid lineage in response to specific cytokines. Cell-type specific receptors are expressed on committed progenitors that bind to other late-acting cytokines that are involved in terminal differentiation of hematopoietic cells. In normal hematopoiesis, these receptors undergo alternative splicing and are developmentally regulated. Splicing changes can significantly affect the structure and function of the receptors resulting in alterations of either the extracellular ligand binding domain or the cytoplasmic signaling domain responsible for cellular growth and differentiation. Most alternatively spliced isoforms generally lose the ability to promote differentiation. Evidently, overexpression of naturally occurring cytokine receptor alternate isoforms are observed in multiple myeloid diseases such as myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and polycythemia vera (PV). The purpose of this review is to introduce the various isoforms of key cytokine receptors that play a crucial role in myeloid development and their potential role in myeloid diseases.