Trib2 Pseudokinase Marks Early CMP Progenitors, and Promotes Granulocytic Plus Erythroid Progenitor Cell Formation

Altered expression of Trib2 pseudokinase has been associated with AML (M2, M4 subtypes) (Cancer Cell, 10: 401), and ectopic expression of Trib2 in hematopoietic progenitors drives myeloid leukemogenesis (Blood, 116: 1321). In addition, inhibition of Trib2 expression by EPO in erythroid progenitors has been demonstrated (Blood, 111: 5390). Beyond this, little is known about Trib2’s expression profiles and roles during normal myelopoiesis. To critically address functional roles, we have generated and characterized a novel Trib2-KO mouse model. Within bone marrow CFU-GM formation faltered, and Trib2-KO Lin^neg progenitors exhibited deficit granulocyte production (with a relative increase in monocytes). This was not associated with significant differences in survival or cell cycle features among developing granulomonocytic cells. Instead, Trib2 levels proved to be heightened among Lin^neg progenitors (and inhibited in GM cells following GMCSF, GCSF or ATRA exposure). This prompted analyses of CMP and early-CMP (eCMP) populations in which RNAseq demonstrated peak Trib2 expression. Furthermore, eCMP and CMP pools were elevated in Trib2-KO mice. Within progenitors of the erythroid lineage, Trib2 expression levels also selectively increased, and in Trib2-KO mice BFUe and CFUe levels were decreased (and RBC plus HGB were diminished). Intriguingly, when Trib2-KO mice were challenged with Flt3L plus GMCSF, BFUe (but not CFU-GM or GEMM) were mobilized to peripheral blood at levels 13.3-fold above wild-type controls. This indicates candidate effects of Trib2 on a proposed BFUe niche. Overall, novel multi-lineage roles for Trib2 are revealed in regulating eCMP pools, GM-CSF populations, balanced granulocytic vs monocytic cell formation, and the production of erythroid progenitor cells.