Poster Presentation 25th Lorne Cancer Conference 2013

Mixl1 expression in human leukemias and lymphomas (#242)

Katherine K Lange 1 , Chee-Kai Chan 1 , Adam H Hart 1
  1. Latrobe Institute for Molecular Science, Bundoora, Vic, Australia

Mixl1 is a homeobox transcription factor expressed only in mesendoderm progenitors within the primitive streak of the gastrulating mouse embryo [1], and is essential for normal development of gut endoderm and cardiac mesoderm [2]. However, overexpression of Mixl1 in adult mouse bone marrow has been shown to block normal differentiation and commitment of haematopoietic progenitors, initiating acute myeloid leukemia (AML) [3]. Recently, human Mixl1 expression was detected in patients with Burkitt lymphoma and diffuse large B-cell lymphoma compared with other types of B-cell non-Hodgkin lymphomas, suggesting that Mixl1 may play a role in human lymphomagenesis [4].

To examine the correlation of Mixl1 upregulation with human blood disorders, we examined Mixl1 expression in samples from myeloid and lymphoid leukemia patients, and lymphoma patients, by qPCR. We found Mixl1 RNA upregulation in patients with myelodysplastic syndrome (6/7), AML (10/16), CML (6/8) and B-cell lymphoma (15/25), with the highest Mixl1-upregulation seen in AML and B-cell lymphoma patients, compared with normal monocyte samples. In order to discover the specific genes regulated by Mixl1 in leukemogenesis, we carried out transcriptional profiling on mouse ES cell lines with inducible Milx1 expression. We found upregulation of two leukemia-related genes - Pou2F1 (Oct1), a transcription factor associated with B-cell lymphomas [5], and Egr1, a zinc-finger transcription factor associated with monocytic differentiation of myeloid leukemic cells [6]. Further understanding these molecular pathways involved in specific instances of leukemias and lymphomas could improve treatment options in the future on a patient-specific basis depending on the expression of particular factors, rather than the disease pathology.

  1. Robb L, Hartley L, Begley CG, et al. Cloning, expression analysis, and chromosomal localization of murine and human homologues of a Xenopus mix gene. Dev Dyn 2000;219:497-504.
  2. Hart AH, Hartley L, Sourris K, et al. Mixl1 is required for axial mesendoderm morphogenesis and patterning in the murine embryo. Development 2002;129:3597-3608.
  3. Glaser S, Metcalf D, Wu L, et al. Enforced expression of the homeobox gene Mixl1 impairs hematopoietic differentiation and results in acute myeloid leukemia. Proc Natl Acad Sci U S A 2006;103:16460-16465.
  4. Drakos E, Rassidakis GZ, Leventaki V, et al. Differential expression of the human MIXL1 gene product in non-Hodgkin and Hodgkin lymphomas. Hum Pathol 2007;38:500-507.
  5. Saez AI, Artiga MJ, Sanchez-Beato M, et al. Analysis of octamer-binding transcription factors Oct2 and Oct1 and their coactivator BOB.1/OBF.1 in lymphomas. Mod Pathol 2002;15:211-220.
  6. Kharbanda S, Nakamura T, Stone R, et al. Expression of the early growth response 1 and 2 zinc finger genes during induction of monocytic differentiation. J Clin Invest 1991;88:571-577.