Ng et al have studied mice with a mutated Erg allele and a normal allele and find that normal steady state hematopoiesis can be maintained in these mice whereas stress-induced self-renewal of hematopoietic stem cells (HSCs) is impaired.1 

Adult HSCs reside in the bone marrow niches and their fate is regulated by transcription factors, cell-cycle regulators, epigenetic modifiers, and signal transduction pathways that are stimulated by external cues.2  One of the transcription factors important for regulation of HSCs is Erg, a member of the ETS family of transcription factors. The first reports suggesting an important role for Erg in the regulation of hematopoiesis came from studies of malignant hematopoiesis. Two initial reports identified Erg as a partner in fusion proteins that were identified in myeloid leukemias.3,4  Since then, additional reports have identified either translocations involving Erg or overexpression of Erg in various types of leukemia (Ng et al and references therein).1  More recently, Erg has been studied in normal hematopoiesis and hematopoietic development. Mice have been generated with a mutation termed Mld2 that disrupts the ability of Erg to transactivate gene expression. Failure of definite hematopoiesis is observed at midgestation in mice homozygous for the ErgMld2 allele.5,6  In this issue of Blood, Ng et al study hematopoiesis in mice heterozygous for the ErgMld2 allele.1  Steady state hematopoiesis is normal in Erg+/Mld2 mice although they exhibit a reduction in Lin-Sca1+cKit+ (LSK) progenitor and stem cells and their HSCs compete poorly with normal bone marrow in competitive repopulation assays. While short-term repopulation was relatively strong, the long-term repopulation defect was profound, suggesting a major defect in the most primitive stem cells but with relatively functional primitive progenitors also supported by normal numbers of CFU-S colonies generated by the mutants. The most profound defects in HSC function were observed during stress hematopoiesis. After treatment with sublethal radiation, the Erg+/Mld2 mice recovered more slowly than normal mice and on serial transplantation, the mutant mice exhibited a profound HSC self-renewal effect and reconstituted poorly. There are also other hematopoietic defects in the mutant mice, particularly low platelet levels that may be due to a role that Erg plays in the differentiation of preMegE progenitors. The defect in platelet production was further increased in double mutant mice when the Erg+/Mld2 mice were mated to Mpl−/− mice (TPO receptor null). The double mutant mice also have a more profound HSC defect and generated bone marrow failure and died prematurely because of hemorrhage and bone marrow aplasia.

Using heterozygous mutant mice that harbor a point mutation in the Erg gene that prevents binding to DNA targets, the authors demonstrate that lower Erg levels can cause a serious HSC defect. Several other transcription factors have also been shown to generate abnormal fate decisions when the concentrations are too low or too high. GATA2 is an example where haploinsufficient GATA2+/− mice exhibit lower levels of immunophenotypic HSCs and reduced competitive transplantation ability.7  Similarly, HOXA10 has dose-dependent effects on HSCs. Thus, intermediate levels of HOXA10 increase self-renewal of HSCs in vitro whereas high levels have no effect on HSC self-renewal.8  The same group that published the Erg+/Mld2 paper discussed here has also shown that trisomy of Erg is required for myeloproliferation in mice with Down syndrome, suggesting that increased gene dosage of Erg is the main factor that predisposes patients with Down syndrome to a myeloproliferative disorder and acute megakaryocytic leukemia.9  Thus the trisomy of Erg has opposite effects on HSCs than the low Erg levels seen in the Erg+/Mld2 mice.

The Erg+/Mld2 mice have one functional Erg allele and a mutant allele that encodes for a molecule that cannot bind the gene targets for this transcription factor. Therefore, it is likely that the Erg+/Mld2 mice represent mutant mice that are haploinsufficient with regard to Erg. The main consequence of this mutation in HSCs is seen under hematopoietic stress when the mutant HSCs show a profound defect, especially during serial transplantation. This defect is probably because of both a reduction in the number of functional HSCs and a self-renewal defect that seems to favor HSC divisions that produce progeny that are not long-term reconstituting HSCs but rather multipotential progenitors or short-term HSCs.

Conflict-of-interest disclosure: The author declares no competing financial interests. ■

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