Page 140 - Haematologica Vol. 109 - July 2024

ARTICLE - Ppm1b regulates HSC homeostasis
We demonstrated that Ppm1b interacted with b-catenin,
and Ppm1b deletion led to the inhibition of Wnt/b-catenin signaling via the dephosphorylation in HSC. Although the role of Wnt/b-catenin signaling in B-cell development has been revealed by LEF1 KO mice that led to a reduction in B cells,53 we did not observe any changes in the phosphoryla- tion of b-catenin and downstream target genes’ expression in Ppm1b-deficient B cells (data not shown). This is consis- tent with our findings that Ppm1b is required for the com- mitment and proliferation of B-biased lymphoid progenitor cells from CLP but not the consequent B-cell differentiation. Given that B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by uncontrolled proliferation of early B-cell progenitors, our work identified Ppm1b as the potential target for the clinical treatment of BCP-ALL.
Our data showed that loss of Ppm1b led to the defect in B-cell but not T-cell development. Indeed, lymphopoiesis is an intricate process that gives rise to all lymphocytes which starts with the commitment of HSC to CLP.54 Even though
Z. Lu et al.
CLP generate T and B cells when properly stimulated,55 it seems that CLP are mainly progenitors for B cells, owing to the limited or negligible T-cell generation from CLP.56,57 By the expression of Ly6D, CLP can be defined as all-lymphoid pro- genitors (Ly6D−), which have the potential to generate T and natural killer cells, and B-cell biased lymphocyte progenitors (Ly6D+).58 Moreover, there are still CLP-independent path- ways of innate T-cell development which are more efficient than CLP.59 Importantly, the changes in lymphocyte counts in the first two weeks after 5-FU were most likely not driven by differentiation from HSC but rather due to lymphocyte death and subsequent homeostatic proliferation, as well as differentiation from more committed progenitors (such as BM CLP or Flt3+ MPP) (Figure 4). Given that PLT and RBC in HN252-treated mice showed mild changes compared to that of the control group, a single 5-FU treatment is prob- ably not sufficient to impair the function of HSC pretreated with the PPM1B inhibitor. These data would rather seem to point toward a CLP-intrinsic effect of PPM1B. However, these
Figure 7. Schematic diagram illustrates the regulatory role of Ppm1b in hematopoietic stem cell self-renewal and B-cell development.
Ppm1b is required for hematopoietic stem cell (HSC) proliferation and early B-cell progenitor differentiation. Loss of Ppm1b led to the decrease of the active b-catenin (non-phosphorylated) that interrupted the Wnt/b-catenin signaling in HSC, which consequently suppressed HSC expansion. CLP: common lymphoid progenitors.
Haematologica | 109 July 2024
2154