Abstract
The MN1 oncogene is deregulated in human acute myeloid leukemia and its overexpression induces proliferation and represses myeloid differentiation of primitive human and mouse hematopoietic cells, leading to myeloid leukemia in mouse models. To delineate the sequences within MN1 necessary for MN1-induced leukemia, we tested the transforming capacity of in-frame deletion mutants, using retroviral transduction of mouse bone marrow. We found that integrity of the regions between amino acids 12 to 458 and 1119 to 1273 are required for MN1’s in vivo transforming activity, generating myeloid leukemia with some mutants also producing T-cell lympho-leukemia and megakaryocytic leukemia. Although both full length MN1 and a mutant that lacks the residues between 12–228 (Δ12–228 mutant) repressed myeloid differentiation and increased myeloproliferative activity in vitro, the mutant lost its transforming activity in vivo. Both MN1 and Δ12–228 increased the frequency of common myeloid progentiors (CMP) in vitro and microarray comparisons of purified MN1-CMP and Δ12–228-CMP cells showed many differentially expressed genes including Hoxa9, Meis1, Myb, Runx2, Cebpa, Cebpb and Cebpd. This collection of immediate MN1-responsive candidate genes distinguishes the leukemic activity from the in vitro myeloproliferative capacity of this oncoprotein.
Highlights
Acute myeloid leukemia (AML) in adults is a leading cause of leukemia-related deaths, and is characterized by uncontrolled proliferation and impaired differentiation of hematopoietic cells that results in accumulated myeloid blasts in the bone marrow and periphery. [1] Tight control of the balance between proliferation and differentiation is essential for the maintenance of normal hematopoeisis
MN1 causes acute myeloid leukemia when overexpressed in mouse hematopoietic stem/progenitor cells (HSPC). [7,12] Its overexpression caused impaired myeloid differentiation, increased proliferation, and increased selfrenewal of primary mouse or human CD34+-HSPC in vitro
In this study we mapped the minimal regions of MN1 necessary for its leukemogenic activity as well as the regions of MN1 that distinguish its leukemic in vivo activity from its in vitro myeloproliferative/self-renewal and differentiation inhibitory activities
Summary
Acute myeloid leukemia (AML) in adults is a leading cause of leukemia-related deaths, and is characterized by uncontrolled proliferation and impaired differentiation of hematopoietic cells that results in accumulated myeloid blasts in the bone marrow and periphery. [1] Tight control of the balance between proliferation and differentiation is essential for the maintenance of normal hematopoeisis. [1,2] These genes mostly control the survival/proliferation/differentiation programs of the hematopoietic stem/progenitor cells (HSPC). Others and we have shown that ectopic expression of MN1 in mouse HSPC (Hematopoietic Stem-Progenitor Cells) causes myeloid leukemia [7,12] and MN1 induces proliferation and inhibits myeloid differentiation of both mouse and human HSPC. We could distinguish expression profiles associated with MN1’s myeloproliferative and differentiation inhibitory effects from its myelo-transforming activity. This was accomplished by comparing the transcriptome of highly purified common myeloid progenitors (CMP) overexpressing MN1 or a MN1 deletion mutant, which induced myeloprolifera-
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