The pathogenesis of mixed-lineage leukemia

Annu Rev Pathol. 2012;7:283-301. doi: 10.1146/annurev-pathol-011811-132434. Epub 2011 Oct 17.

Abstract

Aggressive leukemias arise in both children and adults as a result of rearrangements to the mixed-lineage leukemia gene (MLL) located on chromosome 11q23. MLL encodes a large histone methyltransferase that directly binds DNA and positively regulates gene transcription, including homeobox (HOX) genes. MLL is involved in chromosomal translocations, partial tandem duplications, and amplifications, all of which result in hematopoietic malignancies due to sustained HOX expression and stalled differentiation. MLL lesions are associated with both acute myeloid leukemia and acute lymphoid leukemia and are usually associated with a relatively poor prognosis despite improved treatment options such as allogeneic hematopoietic stem cell transplantation, which underscores the need for new treatment regimens. Recent advances have begun to reveal the molecular mechanisms that drive MLL-associated leukemias, which, in turn, have provided opportunities for therapeutic development. Here, we discuss the etiology of MLL leukemias and potential directions for future therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Genes, Homeobox
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / genetics
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / therapy
  • Myelodysplastic Syndromes / genetics*
  • Myelodysplastic Syndromes / therapy
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Oncogene Proteins, Fusion / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy
  • Translocation, Genetic

Substances

  • Oncogene Proteins, Fusion
  • Myeloid-Lymphoid Leukemia Protein
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase