Mutated NPM1 in combination with overexpression of Meis1 or Hoxa9 is not sufficient to induce acute myeloid leukemia

Abstract

Background

Acute myeloid leukemia (AML) carrying nucleophosmin 1 (NPM1) mutations (NPMc⁺) is regarded as a separate entity of myeloid neoplasms due to its distinct biological and clinical features. However, NPMc⁺ alone displays low leukemogenic activity and cooperating events appear crucial for AML to develop. Dysregulation of homeobox genes, such as HOXA9 and MEIS1, is a common transcriptional signature of NPMc⁺ AML. Furthermore, the pathogenic role for NPMc⁺ in AML remains incompletely understood.

Aim

To elucidate if NPMc⁺ collaborates with Meis1 or Hoxa9 in the evolvement of AML.

Methods

Murine bone marrow cells were genetically engineered to express mutated NPM1 variant A in combination with overexpression of Meis1 or Hoxa9. The capacity of the transduced cells to transform in vitro and to cause leukemia in vivo was then assessed.

Findings and conclusion

There was no synergy between NPMc⁺ and Meis1 or Hoxa9 in causing leukemogenic transformation of murine bone marrow cells, or in inducing AML in a transplantation model. Hence, overexpression of Meis1 or Hoxa9 in combination with NPMc⁺ expression was not sufficient to generate an NPMc⁺ AML mouse model.

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