RESUMEN
Determinants regulating short- and long-term repopulating hematopoietic stem cell (STR-HSC and LTR-HSC) self-renewal remain largely uncharacterized. To gain further insights into HSC self-renewal, we investigated possible genetic interactions between two well-recognized regulators of this process: Bmi1 and Hoxb4. Using complementation and overexpression strategies in mouse HSCs, we document that Bmi1 is not required for the in vivo expansion of fetal HSCs but is essential for the long-term maintenance of adult HSCs. Importantly, we show that Hoxb4 overexpression induces an expansion of Bmi1(-/-)STR-HSCs leading to a rescue of their repopulation defect. In contrast to Hoxb4, we also show that Bmi1 fails to induce HSC expansion ex vivo. Consistent with these results, we report high levels of Angptl3 and Cbx7 in Hoxb4- and Bmi1-transduced cells, respectively. Together, these results support the emerging concept that fate and sustainability of this fate are two critical components of self-renewal in adult stem cells such as HSCs.
Asunto(s)
Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Células Madre Adultas/citología , Células Madre Adultas/metabolismo , Animales , Proliferación Celular , Expresión Génica , Prueba de Complementación Genética , Proteínas de Homeodominio/genética , Ratones , Ratones Noqueados , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Complejo Represivo Polycomb 1 , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Factores de Transcripción/genética , Transducción GenéticaRESUMEN
Using murine Moloney leukemia virus (MMLV)-based proviral insertional mutagenesis, we previously showed a preferential targeting of a small region in the Hoxa gene locus in E2A-PBX1-induced lymphoid leukemia resulting in the overexpression of several Hoxa genes including Hoxa10, Hoxa9 and Hoxa7. This observation suggested a functional interaction between Hox gene overexpression and E2A-PBX1 in lymphoid tumors. To further explore this possibility, we generated a series of compound E2A-PBX1 x Hox transgenic mice and tested the genetic interaction between these genes in the generation of lymphoid leukemia in vivo. Results presented in this report show that the onset of T-cell leukemia is significantly accelerated in E2A-PBX1 x Hoxb4 compound transgenic animals when compared with control E2A-PBX1 or Hoxb4 littermates. Hoxa9 appears less potent than Hoxb4 to accelerate E2A-PBX1-induced T-cell leukemia in mice. E2A-PBX1-induced T-cell leukemias express much higher levels of Hoxa genes than MMLV-induced counterparts, possibly suggesting a contribution of these genes to T-cell transformation by E2A-PBX1. Collectively, these data provide the first genetic evidence showing oncogenic collaboration between E2A-PBX1 and a Hox gene in lymphoid malignancies in vivo and document the specific deregulation of a subgroup of Hoxa genes in these leukemias.
Asunto(s)
Proteínas de Homeodominio/genética , Leucemia de Células T/genética , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción/genética , Animales , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Leucemia de Células T/patología , Ratones , Ratones Transgénicos , Virus de la Leucemia Murina de Moloney/genética , Mutagénesis Insercional/genética , Proteínas de Fusión Oncogénica/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Here we describe hemopoietic chimeras serving as a mouse model for NUP98-HOXA9-induced leukemia, which reproduced several of the phenotypes observed in human disease. Mice transplanted with bone marrow cells expressing NUP98-HOXA9 through retroviral transduction acquire a myeloproliferative disease (MPD) and eventually succumb to acute myeloid leukemia (AML). The NUP98 portion of the fusion protein was shown to be responsible for transforming a clinically silent pre-leukemic phase observed for Hoxa9 into a chronic, stem cell-derived MPD. The co-expression of NUP98-HOXA9 and Meis1 accelerated the transformation of MPD to AML, identifying a genetic interaction previously observed for Hoxa9 and Meis1. Our findings demonstrate the presence of overlapping yet distinct molecular mechanisms for MPD versus AML, illustrating the complexity of leukemic transformation.