Oncogenic interaction between BCR-ABL andNUP98-HOXA9 demonstrated by the use of an in vitro purging culture system

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Abstract
Chronic myelogenous leukemia (CML) is a clonal stem cell disease caused by the BCR-ABL oncoprotein and is characterized, in its early phase, by excessive accumulation of mature myeloid cells, which eventually leads to acute leukemia. The genetic events involved in CML's progression to acute leukemia remain largely unknown. Recent studies have detected the presence of theNUP98-HOXA9 fusion oncogene in acute leukemia derived from CML patients, which suggests that these 2 oncoproteins may interact and influence CML disease progression. Using in vitro purging of BCR-ABL–transduced mouse bone marrow cells, we can now report that recipients of bone marrow cells engineered to coexpressBCR-ABL with NUP98-HOXA9 develop acute leukemia within 7 to 10 days after transplantation. However, no disease is detected for more than 2 months in mice receiving bone marrow cells expressing either BCR-ABL orNUP98-HOXA9. We also provide evidence of high levels ofHOXA9 expressed in leukemic blasts from acute-phase CML patients and that it interacts significantly on a genetic level withBCR-ABL in our in vivo CML model. Together, these studies support a causative, as opposed to a consequential, role forNUP98-HOXA9 (and possibly HOXA9) in CML disease progression.