Distinct requirements of hematopoietic stem cell activity and Nras G12D signaling in different cell types during leukemogenesis.

We previously showed that widespread expression of Nras G12D/G12D from its endogenous locus in mice leads to an acute myeloproliferative disease (MPD) with a complete penetrance, whereas bone marrow-specific expression of Nras G12D/G12D in recipient mice did not result in sustained MPD phenotypes but 100% penetrant acute T-cell lymphoblastic leukemia/lymphoma (TALL). Such a phenotypic switch also is seen in the case of endogenous oncogenic Kras. Two possibilities might account for this observation and they are not necessarily mutually exclusive. First, the MPD phenotypes in primary Nras G12D/G12D mice might be a transient phenomenon attributable to microenvironmental factors that do not necessarily imply the potential for long-term maintenance in a hematopoietic-cell autonomous manner. Second, it is likely that MPD phenotypes are maintained by genetically altered hematopoietic stem cells (HSCs). Nras G12D/G12D signaling might substantially alter HSC behaviors (e.g. induce their proliferative exhaustion) so that these HSCs no longer sustain MPD phenotypes to a lethal stage in recipient mice. Here, we show some preliminary results to support the second hypothesis. Our results suggest that different lineages of hematopoietic cells might have differential requirements of HSC activity and Nras G12D signaling during leukemogenesis.