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  • Whether or not SMO and SMO dependent HH signaling play


    Whether or not SMO and SMO-dependent HH signaling play a role in hematopoiesis is a subject of strong controversy. Obviously, the effects of SMO deletion are highly contextual and dependent on the timing of deletion. transplanted murine Smo−/− fetal liver Sennoside A into sublethally irradiated mice and observed no significant effect of the Smo defect on long-term reconstitution of the bone marrow. However, they noted that the short-term repopulation of the bone marrow by HSCs was impaired (). When challenging the hematopoietic regeneration capacity of these mice by injecting 5-FU, they found reduced regeneration 10days but not 40days after the treatment. Thus, loss of Smo seems to affect short-term progenitors rather than long-term repopulating HSCs (). In contrary, , using a Vav-driven Cre-mediated Smo deletion model, observed a clear defect in long-term HSC function in this mouse model including decreased reconstitution of the bone marrow in transplantation assays. While the above-mentioned reports mostly supported the by-then consensus view that HH signaling is needed in adult hematopoiesis, two seminal studies published back-to-back challenged this view in 2009 when they both suggested its complete dispensability (; ). Both studies were based on use of an inducible conditional Smo knockout model in adult mice. A Cre recombinase under the control of myxovirus-resistance 1 (Mx1) gene promoter (Mx1-Cre) allowed for interferon-inducible Smo deletion by stimulation with polyI:polyC. This deletion of Smo in adult mice did not change their hematopoiesis. Consistently, no differences in peripheral blood counts, colony formation in vitro, and HSC/Ps numbers upon Smo deletion could be detected by the authors of both groups (; ). Strikingly, HSC-specific gene expression signature was preserved in the Smo-deficient HSCs () and pharmacological inhibition of Hh signaling did not affect murine hematopoiesis (). One explanation for these observations might be that despite the expression of Hh upstream elements, Hh signaling activity is shut off in the adult murine hematopoietic system. Indeed, expression of the downstream elements Gli1, Gli2, or Gli3, which serve as a sign for pathway activity, was not detectable in these LSKs and myeloid progenitors (). Focusing on the positive downstream effector Gli1, found that mice with a homozygous LacZ insertion in the first exon of Gli1 displayed an increase in the long-term (LT)-HSC compartment. Glinull LT-HSCs were more quiescent and had a higher engraftment potential upon transplantation. However, in the proliferative progenitor compartment, impaired myeloid differentiation and defective hematopoiesis in response to stress was observed ().
    From HSC to CML Chronic myeloid leukemia (CML) is a myeloproliferative clonal disorder that originates from a transformed hematopoietic stem or multipotent progenitor cell. CML is characterized by the Philadelphia chromosome, resulting from the translocation t(9;22) between chromosomes 22 and 9. The resulting Bcr–Abl fusion gene encodes a constitutively active tyrosine kinase and results in strong malignant hematopoiesis and gross disturbances in the normal hematopoietic bone marrow environment (Sawyers, 1992). Looking at GLI1 and PTCH in CD34+ cells from CML patients, observed higher transcript levels in samples from CML patients compared to those from healthy donors. To further evaluate this finding, they induced a CML-like disorder in mice by introducing a Bcr–Abl retrovirus in fetal liver cells that were either Smo negative (Smo−/−) or heterozygous for Ptch (Ptch+/−). These cells were then transplanted into lethally irradiated recipient mice. The retroviral transduction caused upregulation of Smo in the respective Bcr–Abl-positive cells, with higher efficiency in the Ptch+/− model than in WT. Smo−/− Bcr-Abl cells had a reduced potential for expansion, and the disease developed with longer latency and at lower frequency. Treatment with the Smo inhibitor cyclopamine-induced apoptosis in the leukemic cells ex vivo and reduced their clonogenic potential (). The therapeutic potential of Smo inhibition was then explored in combination with the Abl inhibitor nilotinib, both in vitro and in vivo. In vitro, the combination of both agents induced apoptosis of CML cells while sparing those from healthy donors. In vivo, combination treatment of leukemic mice reduced their tumor burden and prolonged their overall survival (). Analogous findings were made by . When they transplanted Bcr–Abl-transduced hematopoietic Smo−/− or WT progenitors into irradiated mice, the Smo−/− cells caused CML in about half of the recipients and with increased latency, whereas transduced WT cells caused leukemia in almost all recipients. Vice versa, transduction of cells harboring constitutively active Smo strongly accelerated the disease progression. Treatment of the diseased mice with cyclopamine extended their overall survival, and leukemic cells from these treated mice were unable to induce the disease upon subsequent transplantation ().