Page 16 - Haematologica Vol. 109 - July 2024

EDITORIAL M. Alberich-Jorda and L. Macurek
Figure 1. PP2C family protein phosphatases regulating the hematopoiesis. PPM1B and PPM1K promote self-renewal of hemato- poietic stem cells (HSC) through activating WNT/b-catenin and MEIS2 pathways, respectively. In contrast, PPM1D promotes dif- ferentiation of HSC by modulating MTOR, p53 and NOTCH pathways. In addition, PPM1B regulates production of B cells but, surprisingly, is not needed in myeloid lineage.
ering the B-cell leukocytopenia observed in Ppm1bCKO mice, it might be interesting to investigate the potential of PPM1B inhibitor in suppressing B-cell leukemias.
Mechanistically, Lu and colleagues point at deregulation of the Wnt/b-catenin signaling pathway as the underlying cause of the B-cell phenotype present in Ppm1bCKO mice. Neverthe- less, the role of the Wnt/b-catenin signaling pathway in the hematopoietic system is controversial, and discrepancies are justified by the use of different models and approaches.8 Here, Lu and colleagues bring into the field a new player, PPM1B, which by its dephosphorylating action can promote the active form of b-catenin, and thus enhance the activ- ity of this pathway. However, while b-catenin is critical for T-cell,9 B-cell,10 and granulocytic development,11,12 they report alterations only in the B-cell compartment. Thus, we can hypothesize that PPM1B does not act in myeloid progenitors or T cells, or that it does not regulate b-catenin phosphory-
lation uniformly in all hematopoietic cells. Ultimately, since the Wnt/b-catenin signaling pathway is regulated at multi- ple levels and is subjected to spatiotemporal regulations, in the future it will be interesting to investigate the impact of PPM1B on this signaling pathway also in other tissues besides the bone marrow.
In summary, Ser/Thr protein phosphatases of the PP2C family are now emerging as new regulators of hematopoiesis and potential pharmacological targets. Their possible clinical use will depend on the development and careful validation of selective small molecule inhibitors.
Disclosures
No conflicts of interest to disclose.
Contributions
LM wrote the manuscript with the input from MAJ.
Haematologica | 109 July 2024
2030