Molecular Pathogenesis of MLL-associated Leukemias

Overview

Journal Int J Hematol

Specialty Hematology

Date 2005 Aug 18

PMID 16105754

Citations 17

Authors

Mariko Eguchi

Minenori Eguchi-Ishimae

Mel Greaves

Affiliations

Soon will be listed here.

Abstract

Chromosome translocations disrupting the MLL gene are associated with various hematologic malignancies but are particularly common in infant and secondary therapy-related acute leukemias. The normal MLL-encoded protein is an essential component of a supercomplex with chromatin-modulating activity conferred by histone acetylase and methyltransferase activities, and the protein plays a key role in the developmental regulation of gene expression, including Hox gene expression. In leukemia, this function is subverted by breakage, recombination, and the formation of chimeric fusion with one of many alternative partners. Such MLL translocations result in the replacement of the C-terminal functional domains of MLL with those of a fusion partner, yielding a newly formed MLL chimeric protein with an altered function that endows hematopoietic progenitors with self-renewing and leukemogenic activity. This potent impact of the MLL chimera can be attributed to one of 2 kinds of activity of the fusion partner: direct transcriptional transactivation or dimerization/oligomerization. Key unresolved issues currently being addressed include the set of target genes for MLL fusions, the stem cell of origin for the leukemias, the role of additional secondary mutations, and the origins or etiology of the MLL gene fusions themselves. Further elaboration of the biology of MLL gene-associated leukemia should lead to novel and specific therapeutic strategies.

Citing Articles

Clinical, immunophenotypic, and genomic findings of acute myeloid leukemia with RAM immunophenotype: Comparison with other CD56-positive acute leukemias.

Hamdan H, Liu Y, Wang S, Bledsoe J, Chisholm K, Siddon A EJHaem. 2025; 6(1):e1052.

PMID: 39866946 PMC: 11756974. DOI: 10.1002/jha2.1052.

Congenital Acute Myeloid Leukemia with Unique Translocation t(11;19)(q23;p13.3).

Yarbrough C, Bandt S, Hurth K, Wambach J, Rao R, Kulkarni S Cureus. 2015; 7(7):e289.

PMID: 26244121 PMC: 4523210. DOI: 10.7759/cureus.289.

Cytogenetic as an important tool for diagnosis and prognosis for patients with hypocellular primary myelodysplastic syndrome.

Correa de Souza D, de Souza Fernandez C, Camargo A, Apa A, da Costa E, Bouzas L Biomed Res Int. 2014; 2014:542395.

PMID: 25180186 PMC: 4144075. DOI: 10.1155/2014/542395.

Classifying leukemia types with chromatin conformation data.

Rousseau M, Ferraiuolo M, Crutchley J, Wang X, Miura H, Blanchette M Genome Biol. 2014; 15(4):R60.

PMID: 24995990 PMC: 4038739. DOI: 10.1186/gb-2014-15-4-r60.

Genomic characterization of acute leukemias.

Chiaretti S, Gianfelici V, Ceglie G, Foa R Med Princ Pract. 2014; 23(6):487-506.

PMID: 24968698 PMC: 5586934. DOI: 10.1159/000362793.

References

Yokoyama A, Kitabayashi I, Ayton P, Cleary M, Ohki M . Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties. Blood. 2002; 100(10):3710-8. DOI: 10.1182/blood-2002-04-1015. View

Caslini C, Shilatifard A, Yang L, Hess J . The amino terminus of the mixed lineage leukemia protein (MLL) promotes cell cycle arrest and monocytic differentiation. Proc Natl Acad Sci U S A. 2000; 97(6):2797-802. PMC: 16009. DOI: 10.1073/pnas.040574897. View

Minucci S, Maccarana M, Cioce M, De Luca P, Gelmetti V, Segalla S . Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation. Mol Cell. 2000; 5(5):811-20. DOI: 10.1016/s1097-2765(00)80321-4. View

Mikkola H, Fujiwara Y, Schlaeger T, Traver D, Orkin S . Expression of CD41 marks the initiation of definitive hematopoiesis in the mouse embryo. Blood. 2002; 101(2):508-16. DOI: 10.1182/blood-2002-06-1699. View

DiMartino J, Miller T, Ayton P, Landewe T, Hess J, Cleary M . A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL. Blood. 2000; 96(12):3887-93. View

Pineault N, Helgason C, Lawrence H, Humphries R . Differential expression of Hox, Meis1, and Pbx1 genes in primitive cells throughout murine hematopoietic ontogeny. Exp Hematol. 2002; 30(1):49-57. DOI: 10.1016/s0301-472x(01)00757-3. View

So C, Karsunky H, Passegue E, Cozzio A, Weissman I, Cleary M . MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell. 2003; 3(2):161-71. DOI: 10.1016/s1535-6108(03)00019-9. View

Ridge S, Cabrera M, Ford A, Tapia S, RisueNo C, Labra S . Rapid intraclonal switch of lineage dominance in congenital leukaemia with a MLL gene rearrangement. Leukemia. 1995; 9(12):2023-6. View

Mikkers H, Berns A . Retroviral insertional mutagenesis: tagging cancer pathways. Adv Cancer Res. 2003; 88:53-99. DOI: 10.1016/s0065-230x(03)88304-5. View

10.

Lavau C, Luo R, Du C, Thirman M . Retrovirus-mediated gene transfer of MLL-ELL transforms primary myeloid progenitors and causes acute myeloid leukemias in mice. Proc Natl Acad Sci U S A. 2000; 97(20):10984-9. PMC: 27135. DOI: 10.1073/pnas.190167297. View

11.

Lavau C, Du C, Thirman M . Chromatin-related properties of CBP fused to MLL generate a myelodysplastic-like syndrome that evolves into myeloid leukemia. EMBO J. 2000; 19(17):4655-64. PMC: 302066. DOI: 10.1093/emboj/19.17.4655. View

12.

So C, Lin M, Ayton P, Chen E, Cleary M . Dimerization contributes to oncogenic activation of MLL chimeras in acute leukemias. Cancer Cell. 2003; 4(2):99-110. DOI: 10.1016/s1535-6108(03)00188-0. View

13.

Fuks F, Burgers W, Brehm A, Hughes-Davies L, Kouzarides T . DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet. 1999; 24(1):88-91. DOI: 10.1038/71750. View

14.

Tsuzuki S, Seto M, Greaves M, Enver T . Modeling first-hit functions of the t(12;21) TEL-AML1 translocation in mice. Proc Natl Acad Sci U S A. 2004; 101(22):8443-8. PMC: 420413. DOI: 10.1073/pnas.0402063101. View

15.

Greaves M, Maia A, Wiemels J, Ford A . Leukemia in twins: lessons in natural history. Blood. 2003; 102(7):2321-33. DOI: 10.1182/blood-2002-12-3817. View

16.

Felix C, Walker A, Lange B, Williams T, Winick N, Cheung N . Association of CYP3A4 genotype with treatment-related leukemia. Proc Natl Acad Sci U S A. 1998; 95(22):13176-81. PMC: 23750. DOI: 10.1073/pnas.95.22.13176. View

17.

Ross M, Mahfouz R, Onciu M, Liu H, Zhou X, Song G . Gene expression profiling of pediatric acute myelogenous leukemia. Blood. 2004; 104(12):3679-87. DOI: 10.1182/blood-2004-03-1154. View

18.

Armstrong S, Kung A, Mabon M, Silverman L, Stam R, den Boer M . Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell. 2003; 3(2):173-83. DOI: 10.1016/s1535-6108(03)00003-5. View

19.

Tkachuk D, Kohler S, Cleary M . Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell. 1992; 71(4):691-700. DOI: 10.1016/0092-8674(92)90602-9. View

20.

Caslini C, Serna A, Rossi V, Introna M, Biondi A . Modulation of cell cycle by graded expression of MLL-AF4 fusion oncoprotein. Leukemia. 2004; 18(6):1064-71. DOI: 10.1038/sj.leu.2403321. View