NUP98-HOX translocations lead to myelodysplastic syndrome in mice and men

Abstract

The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, dysplasia, and a propensity for transformation to acute myeloid leukemia (AML). A wide spectrum of genetic aberrations has been associated with MDS, including chromosomal translocations involving the NUP98 gene, most commonly leading to fusions of NUP98 with abd-b group HOX genes, including HOXD13. We used vav regulatory elements to direct expression of a NUP98-HOXD13 (NHD13) fusion gene in hematopoietic tissues. NHD13 transgenic mice faithfully recapitulate all the key features of MDS, including peripheral blood cytopenias, bone marrow dysplasia and apoptosis, and transformation to acute leukemia. The MDS that develops in NHD13 transgenic mice is highly lethal; within 14 months, 90% of the mice died of either leukemic transformation or severe anemia and leukopenia due to progressive MDS. These mice provide a preclinical model that can be used for the evaluation of MDS therapy and biology.

Figure 1. Ineffective hematopoiesis and dysplasia in NHD13 mice

A and B H &E stained bone marrow from NHD13 (A) and wild-type (B) mice; total cell number from 2 femurs are indicated. Note densely cellular bone marrow in (A) (original magnification × 100). Examples of a dysplastic micromegakaryocyte (C) and multinucleate erythroblast (D) and hypersegmented neutrophil (E) from NHD13 mouse are shown (original magnification × 1000).

Figure 2. Concurrent erythroid and pre-T leukemia in NHD13 mouse 1018

A and B, peripheral blood (A) and bone marrow (B) demonstrating circulating erythroblasts (arrowheads), nucleated red blood cells (arrows), and replacement of bone marrow with erythroblasts (original magnification × 1000). C and D, section of liver infiltrated with leukemic blasts, stained with H&E (C) or anti-CD3 (D) (original magnification × 100). Note lack of CD3 staining in liver. E and F, section of lung infiltrated with leukemic blasts, stained with H&E (E) or anti-CD3 (F). Note strong CD3 staining in lung (original magnification × 100; inset × 400). (G) Southern blot of leukemic tissue hybridized to a TCRB probe. Note germline band in all lanes, and a clonal rearranged band in the Th and Lu (arrow). CD3 staining and presence of Notch1 mutation in infiltrated tissues is indicated as yes (Y) or no (N). Co, non-transgenic control; Th, thymus; Li, liver; Lu, lung; K, kidney; Sp, spleen.