Ectopic expression of the homeobox gene Cdx2 is the transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia

Abstract

Creation of fusion genes by balanced chromosomal translocations is one of the hallmarks of acute myeloid leukemia (AML) and is considered one of the key leukemogenic events in this disease. In t(12;13)(p13;q12) AML, ectopic expression of the homeobox gene CDX2 was detected in addition to expression of the ETV6-CDX2 fusion gene, generated by the chromosomal translocation. Here we show in a murine model of t(12;13)(p13;q12) AML that myeloid leukemogenesis is induced by the ectopic expression of CDX2 and not by the ETV6-CDX2 chimeric gene. Mice transplanted with bone marrow cells retrovirally engineered to express Cdx2 rapidly succumbed to fatal and transplantable AML. The transforming capacity of Cdx2 depended on an intact homeodomain and the N-terminal transactivation domain. Transplantation of bone marrow cells expressing ETV6-CDX2 failed to induce leukemia. Furthermore, coexpression of ETV6-CDX2 and Cdx2 in bone marrow cells did not accelerate the course of disease in transplanted mice compared to Cdx2 alone. These data demonstrate that activation of a protooncogene by a balanced chromosomal translocation can be the pivotal leukemogenic event in AML, characterized by the expression of a leukemia-specific fusion gene. Furthermore, these findings link protooncogene activation to myeloid leukemogenesis, an oncogenic mechanism so far associated mainly with lymphoid leukemias and lymphomas.

Disruption of ETV6 in intron 2 results in upregulatory and insertional events in childhood acute lymphoblastic leukaemia

“…The authors concluded that activation of proto-oncogenes might be a more common phenomenon in ETV6 associated leukaemia than was previously thought. 30,53 Our case was different in that the promoter in intron 2 was deleted, suggesting that the promoter upstream of exon 1 was the one involved.…”

“…30 The ectopic expression of intact CDX2 rather than the ETV6-CDX2 fusion proved essential for leukaemogenesis. 53 Reports of lymphoid malignancies include a B-cell precursor cell line in which the STL gene at 6q23 was the partner 26 and a case of paediatric pre-B ALL, the BAZ2 gene at 12q13. 29 Our three cases thus add significantly to the lymphoid examples.…”

Review: genetic models of acute myeloid leukaemia

“…Whole BM NA Aggressive AML (100%) Splenomegaly, anaemia undifferentiated myeloblasts in BM, S + PB (Rawat et al, 2004) Abbreviations: ALL, acute lymphocytic leukaemia; AML, acute myeloid leukaemia; APL, acute promyelocytic leukaemia ATRA, all-trans retinoic acid; BM, bone marrow; MPD, myeloproliferative disease; NA, not available; NOD/SCID, non-obese diabetic/severe combined immunodeficiency disease; PB, Peripheral blood; S, spleen; WBC, white blood cell count.…”

The homeobox gene CDX2 is aberrantly expressed and associated with an inferior prognosis in patients with acute lymphoblastic leukemia

“…7 For transduction of Cdx2, cells were co-cultured with irradiated (4000 cGy from a 137 Cs g-radiation) GP þ E86 Cdx2 producer cells. Clonogenicity of short hairpin RNA (shRNA) transduced Nalm6 cells was analyzed in the CFC assay as described earlier (Methocult H4434, Stemcell Technologies, Vancouver, British Colombia, Canada).…”

“…[3][4][5] However, for the majority of ALL cases the molecular mechanisms driving the malignant transformation are unknown. Recently, data from experimental models and gene expression profiling in patients with acute myeloid leukemia (AML) have identified CDX2 as a powerful oncogene when aberrantly expressed in adult hematopoietic progenitor cells: [6][7][8] the 'caudal related homeobox gene' CDX2 belongs to the family of so-called 'ParaHox genes', which also includes CDX1, CDX4 and the GSH2 homeobox gene. 9 Normally expression of CDX2 is tightly regulated in the adult organism, with expression in the intestine but no expression in adult hematopoietic tissue.…”