New frontier in the treatment of anemia
Lindsley F. Kimball Research Institute (LFKRI), New York Blood Center - NYBC, New York, USA.
Erythropoietin (EPO) and its recombinant forms are used for the treatment of anemia, thanks to EPO’s ability to stimulate the differentiation of red blood cell (RBC) precursors into mature RBCs. Patients who may benefit from EPO therapy include those who develop anemia consequent to chronic kidney disease, AIDS, cancer chemotherapy or hematologic disorders (multiple myeloma, myelodysplastic syndromes). Alternative therapeutic options are needed for patients who show poor EPO response or develop other forms of EPO-non-responsive anemia, including hemolysis, sepsis and genetic bone marrow failure.
The recent identification of a key pathway that controls erythroblast survival has paved the way for the formulation of novel therapeutic strategies for those patients who cannot benefit from EPO therapy. Using human CD34+ hematopoietic stem cell (HSC)-derived erythroblasts and P38α conditional knock-out mice, Hu and co-workers demonstrated that the mitogen-activated protein kinase P38α acts as an intrinsic brake during anemia recovery, by self-restraining erythroblast survival and limiting potential excessive erythropoiesis led by erythropoietic signals. Importantly, P38α loss in mice accelerates the recovery of hemolysis and chemotherapy-driven anemia by reducing erythroblast apoptosis. This mechanism is mediated by P38α deficiency-induced activation of JNK, which serves as an EPO-independent pro-survival signal. JNK prevents Cdk1-induced degradation of the epigenetic silencer Ezh2. In turn Ezh2 stabilization decreases the expression of the pro-apoptotic BCL2 family member, Bim, thus promoting erythroblast survival. In parallel, JNK maintains high P53 levels, by increasing protein stability, thus exerting an anti-tumor function. Therefore, in cancer-related anemias, P38α inhibitors, as well as JNK activators, would have the dual benefit of promoting erythropoiesis, by suppression of a pro-apoptotic pathway and activation of a pro-survival one, and also counteracting tumor progression, by increasing P53 levels (in patients with non-mutated P53).
Hu P, Nebreda AR, Hanenberg H, Kinnebrew GH, Ivan M, Yoder MC, Filippi MD, Broxmeyer HE, Kapur R. “P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim”. Nature Communications 2018 Aug 29;9(1):3518. doi: 10.1038/s41467-018-05955-2.