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. 2013 Sep;27(9):1917-20.
doi: 10.1038/leu.2013.77. Epub 2013 Mar 12.

A powerful molecular synergy between mutant Nucleophosmin and Flt3-ITD drives acute myeloid leukemia in mice

A Mupo, L Celani, O Dovey, J L Cooper, C Grove, R Rad, P Sportoletti, B Falini, A Bradley, G S Vassiliou
Free PMC article

A powerful molecular synergy between mutant Nucleophosmin and Flt3-ITD drives acute myeloid leukemia in mice

A Mupo et al. Leukemia. 2013 Sep.
Free PMC article
No abstract available

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Figures

Figure 1
Figure 1
Npm1c and Flt3-ITD collaborate to drive rapid-onset leukemogenesis with frequent occurrence of Flt3 LOH. (a) Npm1 mutant protein (arrow) accumulates in the cytoplasm of spleen cells collected from 3-week-old Npm1c/Flt3-ITD, but not Npm1c or Flt3-ITD single-mutant mice. (b) Kaplan-Mayer survival plots showing the rapid demise of Npm1c/Flt3-ITD mice compared with all other genotypes. (c) Serial blood counts highlight a consistent explosive increase in blood leukocytes counts (WBC) between 4 and 7 weeks in Npm1c/Flt3-ITD mice (left) and the markedly abnormal WBC, platelet count (Plts) and hemoglobin concentration (Hb) of sick leukemic Npm1c/Flt3-ITD mice compared with age-matched control mice. (d) Loss of the Flt3 WT allele in blood DNA from Npm1c/Flt3-ITD AMLs is demonstrated as loss of intensity of the Flt3-WT PCR band. By contrast, constitutional tail DNA shows no LOH. In these three littermates (19.1a–c), the extent of Flt3-LOH associates with the degree of leukocytosis (N=nuclear lysate, C=cytoplasmic lysate, OCI-AML3 lysate as positive control, † nonspecific band).
Figure 2
Figure 2
Expansion of circulating myeloid cells in Npm1c/Flt3-ITD mice culminating to aggressive AML. (a) Representative flow cytometric analysis of peripheral blood from 7-week-old WT, Npm1c, Flt3-ITD and Npm1c/Flt3-ITD mice shows the presence of a low SSC; CD45dim population of immature/blast cells in double mutant mice and (b) an increase in both mature granulocytic (Gr1+/Mac1+) and monocytic (Gr1−/lo/Mac1+) populations. (c) Colony-forming assays of BM cells derived from WT and mutant mice showing a markedly increased replating ability of Npm1c/Flt3-ITD cells compared with other genotypes, indicative of an increased self-renewal potential. As we described before, a lesser increase in replating ability is observed with Npm1c cells.
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