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Grosveld Research: Acute Myeloid Leukemia

In the case of Acute Myeloid Leukemia (AML) characterized by t(12;22), the MN1 gene on 22q11 is fused to the TEL/ETV6 gene on 12p13. TEL is a member of the ETS family of transcription factors, whereas MN1 is a transcriptional coactivator of the RAR/RXR and VDR/RXR nuclear receptor complexes. Oncogenic transformation of murine bone marrow by the leukemia-specific MN1-TEL fusion protein mainly depends on the N-terminal sequences of MN1, which bind the transcriptional coactivators p300 and RAC-3. Mouse bone marrow cells expressing MN1-TEL readily generate immortalized, factor-dependent cell lines in vitro.

The expression of MN1-TEL in transgenic mice predisposes the animals to develop hematopoietic malignancies, but the type of disease depends on the nature of the cooperating mutations. For example, the activation of Notch1 signaling, the inactivation of the p53 tumor suppressor pathway, and the downregulation of the cell cycle regulator pRb in mice results in the development of T-cell lymphoma, whereas the forced expression of HoxA9 in MN1-TEL mice results in the development of AML overexpressing N-Myc. The latter closely mimics the situation in patients with AML whose leukemic cells express MN1-TEL and overexpress HOXA9 and N-MYC.

Experiments designed to assess the cooperation between MN1-TEL and N-MYC in mice showed that forced expression of N-MYC alone is a highly oncogenic event that causes the rapid development of AML, irrespective of whether the mice also expresses MN1-TEL. Subsequent analysis of expression arrays of AML cells from St. Jude patients revealed that the expression of this gene is elevated in more than 34% of patients, suggesting widespread involvement of N-MYC in human AML.

In other studies, we found that the overexpression of MN1 alone in mouse bone marrow rapidly induces a myeloproliferative disease. This bone marrow also readily generates immortalized cell lines in vitro. However, these cell lines have a more differentiated phenotype than those generated using cells that overexpress MN1-TEL. This finding suggests that TEL sequences direct the fusion protein to the regulatory sequences of genes that affect differentiation. Because it had been reported that MN1 is overexpressed in human AML specified by the inv(16) chromosomal aberration, we investigated whether MN1 overexpression cooperates with CBFβ-MYH11, the product of inv(16), in myeloid leukemogenesis in mice and found this to be the case. We also found that MN1 overexpression occurs in other types of myeloid leukemia. Given this cooperation, we believe that MN1 overexpression in inv(16) AML in humans is an important cooperating event in disease development.

Presently, we are identifying genes that are regulated by MN1-TEL and MN1 and are isolating protein complexes containing these oncoproteins. These analyses will provide direct insight into the biochemical mechanisms that mediate the oncogenic effects of MN1-TEL and MN1.

As a side project of the MN1-TEL study, we examined the potential role of the TEL homolog, TEL2/ETV7, in cancer. Normal expression of this gene is restricted to the hematopoietic system, mainly to the B-cell lineages. However, upregulated expression of TEL2/ETV7has been shown in cancer cells and cell lines, suggesting that this protein has a causal role in neoplasia.

Indeed, we showed that forced expression of TEL2/ETV7 blocks vitamin-D3–induced differentiation of U937 cells, and mice overexpressing the gene in bone marrow develop a myeloproliferative disease. Also, forced TEL2/ETV7 expression cooperates strongly with c-Myc overexpression in a murine model of Burkitt lymphoma. Finally, the gene is overexpressed in more than 30% of pediatric acute lymphoblastic leukemias.  Currently, we are addressing how TEL2/ETV7 stimulates cell proliferation. Our preliminary data suggest that a novel, unexpected mechanism is involved.