Page 15 - Haematologica Vol. 109 - July 2024

EDITORIAL
Hematopoietic stem cell fate under the influence of Ser/ Thr protein phosphatases
Meritxell Alberich-Jorda and Libor Macurek
Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska, Prague, Czech Republic
Hematopoietic stem cells (HSC) are multipotent cells capable of unlimited self-renewal and are essential for production of blood and immune cells throughout life. HSC reside in a quiescent state in the bone marrow and proliferate only after certain stimuli. Failure in wakening these quiescent cells may result in hematologic defects, and, therefore, this process is tightly regulated by multiple signaling pathways. Recent research suggests that Ser/ Thr protein phosphatases may be involved in HSC biology more than previously anticipated.
In this issue, Lu and colleagues show that protein phospha- tase PPM1B controls homeostasis of HSC through regulation of the Wnt/b-catenin signaling pathway. Using a transgenic Ppm1bCKO mouse model with VAV-Cre mediated conditional deletion of exon 2 of the Ppm1b gene in hematopoietic cells, they showed that PPM1B is necessary for proliferation of HSC.1 Impaired functionality of HSC in Ppm1bCKO animals was further demonstrated by limiting dilution assays and serial transplantation experiments. Data from the animal model were recapitulated in vitro using the small mole- cule inhibitor of PPM1B (HN2522), as well as by depletion of PPM1B by RNA interference. In addition, Ppm1bCKO mice also exhibited alterations in common lymphoid progenitors, which resulted in B-cell leukocytopenia, whereas the my- eloid lineage was unaffected. Furthermore, RNAseq analysis from Lineage- Sca-1+ c-Kit+ (LSK) hematopoietic stem and progenitor cells revealed that several signaling pathways, including WNT, were dysregulated in Ppm1bCKO animals. In particular, several downstream targets of b-catenin, including Fzd1, Jun, Camk2b, Lrp5, Ccnd1 and Gpc4, were down-regulated upon the deletion of Ppm1b suggesting that the defect in HSC may be caused by suppression of WNT signaling. Indeed, LSK cells from Ppm1bCKO animals showed increased levels of the inactive form of b-catenin, which is phosphorylated at Ser33/37/Thr41. Finally, the Authors nicely demonstrated that stimulation of the WNT
pathway by BML-284 rescued the phenotypes in Ppm1bCKO mice, supporting the conclusion that PPM1B controls HSC through stimulation of the WNT pathway.
PPM1B belongs to a conserved PP2C family of Ser/Thr phos- phatases that require binding of manganese/magnesium ions for their activity. They function as single subunit en- zymes and their substrate specificity is influenced by in- ternal linker regions. Interestingly, other members of this conserved phosphatase family have also been implicated in hematopoiesis. In particular, mitochondrial PPM1K was pro- posed to regulate branched amino acid catabolism in HSC and loss of PPM1K impaired maintenance of the HSC pool.3 In addition, loss of the nuclear PPM1D (also called WIP1) phosphatase caused mTORC-dependent expansion of the HSC compartment in Ppm1d-/- animals, whereas truncating gain-of-function mutations in PPM1D reduced self-renewal of HSC.4,5 Interestingly, the truncated PPM1D stimulates HSC survival after genotoxic stress by inhibiting the p53 pathway and can promote therapy-induced acute myeloid leukemia.5,6 Altogether, these observations point at the crucial role of Ser/Thr phosphatases in the regulation of HSC properties and their potential contribution to the development of hematologic disorders. In fact, several phosphatases have been implicated in hematologic malignancies as well as in solid tumors, and may represent attractive pharmacological targets in future clinical interventions. The development of small molecule inhibitors to protein phosphatases is chal- lenging, and few compounds show satisfactory specificity and efficiency in cellular and animal models. For example, the selective PPM1D inhibitor GSK2830371 suppressed the growth of p53-positive cancer cells in vitro and in animal models.5-7 In the present study, Lu and colleagues used a new PPM1B inhibitor (HN252), proved its efficiency in animal models, and elegantly validated its specificity in the Ppm- 1bCKO animals.1,2 This tool will be invaluable for exploring the functions of PPM1B in several systems. Additionally, consid-
Haematologica | 109 July 2024
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Correspondence: L. Macurek libor.macurek@img.cas.cz
Received: Accepted: Early view:
February 22, 2024. February 27, 2024. March 7, 2024.
https://doi.org/10.3324/haematol.2024.285040
©2024 Ferrata Storti Foundation Published under a CC BY-NC license