Abstract:
GATA1 plays a critical role in differentiation, proliferation, and apoptosis during erythropoiesis. We developed a Gata1 knock-down allele (Gata1.05) that results in GATA1 expression at 5% of endogenous level. In female mice heterozygous for both the Gata1.05 and wild-type alleles, we observed a predisposition to erythroblastic leukemia three to six months after birth. Since no male Gata1.05 progeny survive gestation, we originally maintained heterozygous females in a mixed genetic background of C57BL/6J and DBA/2 strains. Around 30% of these mice reproducibly develop leukemia, but the other subset did not develop leukemia, even though they harbor a high number of preleukemic erythroblasts. These observations prompted us to hypothesize that there may be potential influence of genetic determinants on the progression of Gata1.05-driven hematopoietic precursors to full-blown leukemia. In an initial examination of Gata1.05/X mice backcrossed into C3H/He, BALB/c, DBA/2, C57BL/6J and 129X1/SvJ strains, we discerned that the backgrounds of C57BL/6J and 129X1/SvJ significantly expedited leukemia onset in Gata1.05/X mice. Conversely, backgrounds of C3H/He, BALB/c and DBA/2 did not substantially modify the effect of the Gata1 mutation. This indicates the existence of genetic modifiers that accentuate Gata1.05 leukemogenesis. Subsequent cohort studies evaluated Gata1.05/X mice within mix backgrounds of BALB/c:129X1/SvJ and BALB/c:C57BL/6J. In these settings, Gata1.05-driven leukemia manifested in autosomal dominant patterns within the 129X1/SvJ background and in autosomal recessive patterns within C57BL/6J background. To the best of our knowledge, this study provides the inaugural evidence of genetic modifiers that can reshape the outcome based on leukemia-associated gene signatures.
摘要:
GATA1在分化中起着至关重要的作用,扩散,和红细胞生成过程中的细胞凋亡。我们开发了Gata1敲低等位基因(Gata1.05),导致GATA1在内源性水平的5%表达。在Gata1.05和野生型等位基因杂合的雌性小鼠中,我们观察到出生后3到6个月的红细胞白血病的易感性。由于没有雄性Gata1.05后代在妊娠中存活,我们最初在C57BL/6J和DBA/2菌株的混合遗传背景下维持杂合雌性。这些小鼠中约有30%可重复发展为白血病,但是另一个子集没有发展为白血病,尽管他们藏有大量的白血病前期红细胞。这些观察结果促使我们假设,遗传决定子可能对Gata1.05驱动的造血前体向全面白血病的进展产生潜在影响。在Gata1.05/X小鼠回交C3H/He的初步检查中,BALB/c,DBA/2、C57BL/6J和129X1/SvJ菌株,我们发现,C57BL/6J和129X1/SvJ的背景显着加速了Gata1.05/X小鼠的白血病发作。相反,C3H/He的背景,BALB/c和DBA/2基本上没有改变Gata1突变的作用。这表明存在增强Gata1.05白血病发生的遗传修饰剂。随后的队列研究评估了BALB/c:129X1/SvJ和BALB/c:C57BL/6J混合背景下的Gata1.05/X小鼠。在这些设置中,Gata1.05驱动的白血病表现为129X1/SvJ背景内常染色体显性遗传模式和C57BL/6J背景内常染色体隐性遗传模式。据我们所知,这项研究提供了遗传修饰剂的初步证据,这些遗传修饰剂可以重塑基于白血病相关基因特征的结局.