Introduction

MLL

Source (Entrez Gene) 

 MLL in disease

Recurring chromosomaltranslocations involving chromosome 11, band q23, have been observed in acutelymphoid leukemias and especially in acute myeloid leukemias (AML). The breakpoints in four11q23 translocations associated with leukemia were contained within a yeastartificial chromosome (YAC) clone bearing the Cd3d and Cd3g gene loci. Within this YAC, a transcription unit that spans the breakpoint junctions of 3 of these translocations, 4;11, 9;11, and 11;19 was identified. 2 other relatedtranscripts were described, that were upregulated in a translocation cell line.They named the gene MLL for myeloid/lymphoid, or mixed lineage, leukemia.

The types of acutelymphoblastic leukemia and acute myeloid leukemia that are particularlyassociated with translocations involving 11q23 are acute monoblastic leukemia(AML-M5) and acute myelomonocytic leukemia (AMML-M4).

The MLL gene spans the breakpoint in translocationsinvolving 11q23 which are responsible for approximately 70% of AML and ALL ininfants and are also observed in treatment-related leukemias, especially inpatients previously treated with drugs inhibiting topoisomerase II demonstratedthat unique or clonotypic MLL-AF4 genomic fusion sequences were detectable inneonatal blood spots from individuals who developed ALL at ages 5 months to 2years, thus providing unequivocal evidence for a prenatal initiation of acuteleukemia in young patients. Common subtypes due to other translocation fusiongenes can be expected to have a similar prenatal initiation. Epidemiologicstudies suggested that maternal exposure to various substances such aspesticides, marijuana, or an excess of flavonoids (naturally occurringinhibitors of topoisomerase II) might be associated with acute leukemia ininfants.

Clustering algorithmsshowed that lymphoblastic leukemias with MLL translocations can clearly beseparated from conventional acute lymphoblastic and acute myelogenousleukemias. They proposed that they constitute a distinct disease, denoted asMLL, and showed that the differences in gene expression are robust enough toclassify leukemias correctly as MLL versus acute lymphoblastic leukemia oracute myelogenous leukemia. 

Source (OMIM) 

Animal Models of MLL

Yu et al. (1995)

• Mll deletion in mice was embryonic lethal.
• Mll+/- mice had retarded growth, hemopoietic abnormalities and bidirectionalhomeotic transformation of the axial skeleton (with altered Hox geneexpression), as well as sternal malformations.

Yamashita et al. (2006)

• Role of MLL in the immune system using Mll +/- mice:
  • Mll+/- Cd4-positive T cells differentiated normally into antigen-specific effectorTh1 and Th2 cells in vitro, but the ability of memory Th2 cells to produce Th2cytokines was dramatically decreased.
  • Histone methylation and acetylation at Th2 cytokine gene loci was not maintained in Mll+/- memory Th2 cells. Levels of Gata3 mRNA were normal in Mll +/- effector Th2cells, but they were substantially decreased in Mll +/- memory Th2 cells; mRNA levels of other transcription factors were not affected in Mll +/- memory Th2cells. Histone modifications of Gata3 were also aberrant in Th2 cell lines inwhich Mll expression had been knocked down by small interfering RNA,
  • Ovalbumin-inducedallergic eosinophilic inflammation was reduced in Mll +/- Th2 cell-transferred mice.

Barabe et al. (2007)

• Upon transplantation into immunodeficient mice, primitive humanhematopoietic cells expressing a mixed-lineage leukemia (MLL) fusion gene generated myeloid or lymphoid acute leukemias, with features that recapitulated human diseases. clinical hallmarks of MLL leukemias.

McMahon et al. (2007)

• Fetal liver from Mll-knockout mouse embryos showed defects in the hematopoietic stemand progenitor pool, including reductions in long-term and short-termhematopoietic stem cell numbers and a decrease in the quiescent hematopoietic stem cell fraction.

• Adult mice with conditional Mll knockout had no apparent abnormalities in maturehematopoietic cells in bone marrow, spleen, and thymus. However, conditionalMll-knockout bone marrow cells produced reduced numbers of colony-forming unitsand showed reduced ability to compete in hematopoietic reconstitution assays.

Source (OMIM)