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.

The Critical Role of TRIB2 in Cancer and Therapy Resistance

“…At the level of hematopoiesis TRIB2 plays an important role mainly through the degradation of C/EBP-α. It has been observed that TRIB2 is overexpressed during thymus development, and in B cells, natural killers, and CD4+ T cells and to a lesser degree in CD8+ T cells [ 19 ]. Additionally, TRIB2 is expressed in early hematopoietic progenitors and erythroid precursors, and the deletion of TRIB2 mainly affected erythroid lineage development.…”

“…In the hematopoietic system, TRIB2 expression is important for lymphoid and erythroid lineages, as it is highly expressed in lymphoid populations, including B, T and NK cells, and moderately expressed in common myeloid progenitor (CMP) and in megakaryocyte–erythroid progenitors (MEP). Conversely, TRIB1 and TRIB3, are more abundant in myeloid lineage and primitive stem cells, respectively [ 19 ]. Although TRIB2 function is fundamental in lymphoid lineage, it is associated with both acute myeloid (AML) and acute lymphoblastic leukemias (ALL).…”

“…However, the expression of the three TRIBs and their functional role depends on the tissue and cell type in which they are expressed [ 17 , 18 ]. In hematopoiesis, the expression of TRIB1 is higher in myeloid cells, compared to TRIB2 or TRIB3 that are more expressed in B cells and dormant hemopoietic stem cells, respectively [ 19 ]. Furthermore, each member of the Tribbles family has been shown to exert specific physiological functions.…”

Pseudokinases: a tribble‐edged sword

“…The first role for TRIB proteins in haematopoiesis showed that TRIB2 could control the maturation and function of the myeloid and lymphoid lineages in response to cytokines including SCF, G‐CSF, GM‐CSF and M‐CSF . Differential expression of the three TRIB pseudokinases in haematopoietic cells highlights nonredundant and lineage‐specific functions in this system; TRIB1 is expressed most highly in the myeloid lineage, TRIB2 in the lymphoid lineage, and TRIB3 consistently across all haematopoietic cells .…”

Tribbles-1 Expression and Its Function to Control Inflammatory Cytokines, Including Interleukin-8 Levels are Regulated by miRNAs in Macrophages and Prostate Cancer Cells

“…At the transcript level, TRIB1 is highly unstable, reported to have an mRNA half-life shorter than 1 hour (12). TRIB1 expression is also highly variable among different cell types and tissues, suggesting it might be subject to cell type-dependent posttranscriptional regulation (13,14). In fact, the 2kb long, 3'untraslated region (3'UTR) of TRIB1 mRNA represents more than 50% of the entire sequence and is highly conserved among different animal species.…”