Inverse and correlative relationships between TRIBBLES genes indicate non-redundant functions during normal and malignant hemopoiesis

Abstract

TRIBBLES pseudokinases (TRIB1, TRIB2, and TRIB3) are important regulators of normal and malignant hemopoiesis. The relative abundance of each TRIBBLES family member may be important for distinct oncogenic or tumor suppressor functions. We map the expression profiles of TRIB1, TRIB2, and TRIB3 in human and murine hemopoietic stem, progenitor and mature cells, and in human leukemia datasets. Our data show that TRIB1-TRIB2 have an inverse expression relationship in normal hemopoiesis, whereas TRIB1-TRIB3 have a positive correlation. We reveal that TRIB3 expression is high in the dormant hemopoietic stem cell (HSC) population, implicating a novel role for TRIB3 in stem cell quiescence. These analyses support a non-redundant role for each TRIBBLES member during normal hemopoietic differentiation. We show that TRIB1-TRIB2 display a significant negative correlation in myelodysplastic syndrome and acute myeloid leukemia (AML) subtypes, but not in acute lymphoid leukemia. This inverse relationship is specific to certain subtypes of AML. A positive correlation exists in different leukemia subtypes between TRIB1-TRIB3. The TRIB1-TRIB2 and TRIB1-TRIB3 correlations are consistent with a correlative relationship with C/EBP transcription factor family members. Our results have implications for the development of strategies to therapeutically target these genes in different types of leukemia.