Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis

Abstract

The coincident downregulation of NR4A1 and NR4A3 has been implicated in myeloid leukemogenesis, but it remains unknown how these two genes function in myeloid cells and how their combined downregulation promotes myeloid leukemogenesis. Since NR4A1 abrogation is thought to confer a survival and proliferation advantage to myeloid cells, we hypothesized that downregulation of NR4A3 may have a complementary effect on myeloid cell differentiation. First, we tested the association between differentiation status of leukemic cells and NR4A3 expression using two large clinical datasets from patients with different acute myeloid leukemia (AML) subtypes. The analysis revealed a close association between differentiation status and different subtypes of AML Then, we probed the effects of differentiation-inducing treatments on NR4A3 expression and NR4A3 knockdown on cell differentiation using two myeloid leukemia cell lines. Differentiation-inducing treatments caused upregulation of NR4A3, while NR4A3 knockdown prevented differentiation in both cell lines. The cell culture findings were validated using samples from chronic myeloid leukemia (CML) patients at chronic, accelerated and blastic phases, and in acute promyelocytic leukemia (APL) patients before and after all trans-retinoic acid (ATRA)-based differentiation therapy. Progressive NR4A3 downregulation was coincident with impairments in differentiation in patients during progression to blastic phase of CML, and NR4A3 expression was increased in APL patients treated with ATRA-based differentiating therapy. Together, our findings demonstrate a tight association between impaired differentiation status and NR4A3 downregulation in myeloid leukemias, providing a plausible mechanistic explanation of how myeloid leukemogenesis might occur upon concurrent downregulation of NR4A1 and NR4A3.

OMICS Analyses Unraveling Related Gene and Protein-Driven Molecular Mechanisms Underlying PACAP 38-Induced Neurite Outgrowth in PC12 Cells

“…As for the projection elongation effect, the enhanced expression of Nur77 has been observed during NGF-induced projection elongation [ 25 ], and nur77 knockdown inhibits neurite outgrowth [ 26 ]. Similarly, the forced expression of NR4A3 has been reported to elongate neurites [ 27 ]; NR4A3 expression is upregulated by differentiation inducers, and downregulation of NR4A3 expression impairs cell differentiation [ 28 ]. Thus, Nr4A1 and NR4A3 may play an important role in the projection elongation effect of PACAP.…”

Structural Perspective of NR4A Nuclear Receptor Family and Their Potential Endogenous Ligands

“…31) In contrast, the coincidental downregulation of NR4A1 and NR4A3 was reported in myeloid leukemogenesis. 24) Such information suggests that these 2 receptors of the NR4A family are related to each other, with similar pathological roles.…”

“…Although the nuclear receptor family, nuclear receptor subfamily 4 group A (NR4A), consisting of three members, 6) NR4A1, NR4A2, and NR4A3 (old annotations are Nur77, TR3, or NGFI-B, 7) Nurr1, 8) and NOR1 9) ) are orphan receptors, they are promising therapeutic targets in immune diseases, [10][11][12][13] neurological diseases, [14][15][16][17][18][19] and cancer. [20][21][22][23][24] They have been classified as immediate-early genes whose expressions are tightly regulated by extracellular signals. In addition, as shown in Supplementary Fig.…”