Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1

• Published in: Blood 2003-06, Vol.101 (11), p.4529-4538
• Main Authors: Pineault, Nicolas, Buske, Christian, Feuring-Buske, Michaela, Abramovich, Carolina, Rosten, Patty, Hogge, Donna E., Aplan, Peter D., Humphries, R. Keith
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Biological and medical sciences; Bone Marrow Cells - metabolism; Bone Marrow Transplantation; Cell Transformation, Neoplastic; Drug toxicity and drugs side effects treatment; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - physiology; Humans; Leukemia, Myeloid - etiology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Myeloid Ecotropic Viral Integration Site 1 Protein; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - physiology; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - physiology; Pharmacology. Drug treatments; Survival Rate; Toxicity: blood; Transduction, Genetic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-08-2484

HOX genes, notably members of the HOXA cluster, and HOX cofactors have increasingly been linked to human leukemia. Intriguingly, HOXD13, a member of the HOXD cluster not normally expressed in hematopoietic cells, was recently identified as a partner of NUP98 in a t(2;11) translocation associated with t-AML/MDS. We have now tested directly the leukemogenic potential of the NUP98-HOXD13 t(2; 11) fusion gene in the murine hematopoietic model. NUP98-HOXD13 strongly promoted growth and impaired differentiation of early hematopoietic progenitor cells in vitro; this effect was dependent on the NUP98 portion and an intact HOXD13 homeodomain. Expression of the NUP98-HOXD13 fusion gene in vivo resulted in a partial impairment of lymphopoiesis but did not induce evident hematologic disease until late after transplantation (more than 5 months), when some mice developed a myeloproliferative-like disease. In contrast, mice transplanted with bone marrow (BM) cells cotransduced with NUP98-HOXD13 and the HOX cofactor Meis1 rapidly developed lethal and transplantable acute myeloid leukemia (AML), with a median disease onset of 75 days. In summary, this study demonstrates that NUP98-HOXD13 can be directly implicated in the molecular process leading to leukemic transformation, and it supports a model in which the transforming properties of NUP98-HOXD13 are mediated through HOX-dependent pathways.