A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL

J. F. DiMartino, T. Miller, P. M. Ayton, T. Landewe, Jay Hess, M. L. Cleary, A. Shilatifard

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

The t(11;19)(q23;p13.1) chromosomal translocation in acute myeloid leukemias fuses the gene encoding transcriptional elongation factor ELL to the MLL gene with consequent expression of an MLL-ELL chimeric protein. To identify potential mechanisms of leukemogenesis by MLL-ELL, its transcriptional and oncogenic properties were investigated. Fusion with MLL preserves the transcriptional elongation activity of ELL but relocalizes it from a diffuse nuclear distribution to the nuclear bodies characteristic of MLL. Using a serial replating assay, it was demonstrated that the MLL-ELL chimeric protein is capable of immortalizing clonogenic myeloid progenitors in vitro after its retroviral transduction into primary murine hematopoietic cells. However, a structure-function analysis indicates that the elongation domain is not essential for myeloid transformation because mutants lacking elongation activity retain a potent ability to immortalize myeloid progenitors. Rather, the highly conserved carboxyl terminal R4 domain is both a necessary and a sufficient contribution from ELL for the immortalizing activity associated with MLL-ELL. The R4 domain demonstrates potent transcriptional activation properties and is required for transactivation of a HoxA7 promoter by MLL-ELL in a transient transcriptional assay. These data indicate that neoplastic transformation by the MLL-ELL fusion protein is likely to result from aberrant transcriptional activation of MLL target genes. Thus, in spite of the extensive diversity of MLL fusion partners, these data, in conjunction with previous studies of MLL-ENL, suggest that conversion of MLL to a constitutive transcriptional activator may be a general model for its oncogenic conversion in myeloid leukemias. (C) 2000 by The American Society of Hematology.

Original languageEnglish (US)
Pages (from-to)3887-3893
Number of pages7
JournalBlood
Volume96
Issue number12
StatePublished - Dec 1 2000
Externally publishedYes

Fingerprint

Transcriptional Activation
Elongation
Fusion reactions
Transcriptional Elongation Factors
Assays
Genes
Chemical activation
Genetic Translocation
Proteins
Gene encoding
Myeloid Leukemia
Electric fuses
Acute Myeloid Leukemia
In Vitro Techniques

ASJC Scopus subject areas

  • Hematology

Cite this

DiMartino, J. F., Miller, T., Ayton, P. M., Landewe, T., Hess, J., Cleary, M. L., & Shilatifard, A. (2000). A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL. Blood, 96(12), 3887-3893.

A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL. / DiMartino, J. F.; Miller, T.; Ayton, P. M.; Landewe, T.; Hess, Jay; Cleary, M. L.; Shilatifard, A.

In: Blood, Vol. 96, No. 12, 01.12.2000, p. 3887-3893.

Research output: Contribution to journalArticle

DiMartino, JF, Miller, T, Ayton, PM, Landewe, T, Hess, J, Cleary, ML & Shilatifard, A 2000, 'A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL', Blood, vol. 96, no. 12, pp. 3887-3893.
DiMartino JF, Miller T, Ayton PM, Landewe T, Hess J, Cleary ML et al. A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL. Blood. 2000 Dec 1;96(12):3887-3893.
DiMartino, J. F. ; Miller, T. ; Ayton, P. M. ; Landewe, T. ; Hess, Jay ; Cleary, M. L. ; Shilatifard, A. / A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL. In: Blood. 2000 ; Vol. 96, No. 12. pp. 3887-3893.
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abstract = "The t(11;19)(q23;p13.1) chromosomal translocation in acute myeloid leukemias fuses the gene encoding transcriptional elongation factor ELL to the MLL gene with consequent expression of an MLL-ELL chimeric protein. To identify potential mechanisms of leukemogenesis by MLL-ELL, its transcriptional and oncogenic properties were investigated. Fusion with MLL preserves the transcriptional elongation activity of ELL but relocalizes it from a diffuse nuclear distribution to the nuclear bodies characteristic of MLL. Using a serial replating assay, it was demonstrated that the MLL-ELL chimeric protein is capable of immortalizing clonogenic myeloid progenitors in vitro after its retroviral transduction into primary murine hematopoietic cells. However, a structure-function analysis indicates that the elongation domain is not essential for myeloid transformation because mutants lacking elongation activity retain a potent ability to immortalize myeloid progenitors. Rather, the highly conserved carboxyl terminal R4 domain is both a necessary and a sufficient contribution from ELL for the immortalizing activity associated with MLL-ELL. The R4 domain demonstrates potent transcriptional activation properties and is required for transactivation of a HoxA7 promoter by MLL-ELL in a transient transcriptional assay. These data indicate that neoplastic transformation by the MLL-ELL fusion protein is likely to result from aberrant transcriptional activation of MLL target genes. Thus, in spite of the extensive diversity of MLL fusion partners, these data, in conjunction with previous studies of MLL-ENL, suggest that conversion of MLL to a constitutive transcriptional activator may be a general model for its oncogenic conversion in myeloid leukemias. (C) 2000 by The American Society of Hematology.",
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AU - Shilatifard, A.

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