Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties

Yokoyama, Akihiko; Kitabayashi, Issay; Ayton, Paul M.; Cleary, Michael L.; Ohki, Masafumi

doi:10.1182/blood-2002-04-1015

Cited by 150 publications

(132 citation statements)

References 45 publications

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“…Recent studies have shown that MLL undergoes proteolytic processing shortly after translation and that this cleavage divides the protein into a larger N-terminal portion (320 kDa) and a smaller C-terminal part (180 kDa) [Yokoyama et al, 2002;Hsieh et al, 2003b]. The enzyme responsible for this processing is Taspase 1, and two cleavage sites are located just upstream of the activation domain [Hsieh et al, 2003a] (Fig.…”

Section: Many Pieces Of the Puzzlementioning

confidence: 99%

MLL: How complex does it get?

Popovic

Zeleznik‐Le

2005

J of Cellular Biochemistry

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The mixed lineage leukemia (MLL) gene encodes a very large nuclear protein homologous to Drosophila trithorax (trx). MLL is required for the proper maintenance of HOX gene expression during development and hematopoiesis. The exact regulatory mechanism of HOX gene expression by MLL is poorly understood, but it is believed that MLL functions at the level of chromatin organization. MLL was identified as a common target of chromosomal translocations associated with human acute leukemias. About 50 different MLL fusion partners have been isolated to date, and while similarities exist between groups of partners, there exists no unifying property shared by all the partners. MLL gene rearrangements are found in leukemias with both lymphoid and myeloid phenotypes and are often associated with infant and secondary leukemias. The immature phenotype of the leukemic blasts suggests an important role for MLL in the early stages of hematopoietic development. Mll homozygous mutant mice are embryonic lethal and exibit deficiencies in yolk sac hematopoiesis. Recently, two different MLL-containing protein complexes have been isolated. These and other gain-and loss-of-function experiments have provided insight into normal MLL function and altered functions of MLL fusion proteins. This article reviews the progress made toward understanding the function of the wild-type MLL protein. While many advances in understanding this multifaceted protein have been made since its discovery, many challenging questions remain to be answered. J. Cell. Biochem. 95: 234-242, 2005. ß 2005 Wiley-Liss, Inc.

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Section: Many Pieces Of the Puzzlementioning

confidence: 99%

MLL: How complex does it get?

Popovic

Zeleznik‐Le

2005

J of Cellular Biochemistry

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“…The full-length MLL protein is cleaved by taspase, an aspartic protease, into two fragments MLL-N and MLL-C, which are both core components of MLL complex [13][14][15]. A growing body of evidence has revealed MLL to be a member of a large multi-protein complex that contains proteins involved in chromatin modification/remodeling.…”

Section: Mll and Its Role In Normal Hematopoiesismentioning

confidence: 99%

Disordered epigenetic regulation in MLL-related leukemia

et al. 2012

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Leukemias bearing rearrangements of chromosome 11q23 are of particular interest due to their unique clinical and biological characteristics. 11q23 abnormalities occur in up to 70 % of infant leukemias, and about 10 % of adult acute myelogenous leukemias (AML). Two major rearrangements of the MLL gene are found in MLL-related leukemia. The most common of these is balanced translocations in which the N-terminal portion of MLL is fused to the C-terminus of the translocation partner. To date, nearly 100 different chromosome bands have been described in rearrangements involving MLL, and more than 70 known fusion partners of MLL have been cloned and characterized at the molecular level. Another major aberration of the MLL gene creates a repeat within the N-terminal MLL resulting in an internal partial tandem duplication (PTD). As a consequence, an extra amino-terminus is added in-frame to full-length MLL, resulting in leukemogenic MLL-PTD. MLL-PTD occurs predominantly in myeloid dysplasia syndromes, secondary AML (s-AML), and de novo AML. The presence of an MLL rearrangement generally confers a poor prognosis. MLL fusions and MLL-PTD are transcriptional regulators that take control of targets normally controlled by MLL, with the clustered HOX homeobox genes as prominent examples. Several epigenetic regulators that modify DNA or histones have been implicated in MLL fusion driven leukemogenesis, including DNA methylation, histone acetylation, and histone methylation. Recently, the histone methyltransferase DOT1L, the bromodomain and extra-terminal (BET) family member BRD4, and the MLL-interacting protein Menin have emerged as important mediators of MLL fusion-mediated leukemic transformation. The clinical development of targeted inhibitors of these epigenetic regulators has heralded promise for the treatment of MLL fusion leukemia. Although the biological function and molecular mechanism for MLL-PTD remains largely unknown, based on the primary protein structure of MLL-PTD and the knowledge gained so far from MLL fusions, newly developed inhibitors of epigenetic regulators could potentially also prove effective in the treatment of MLL-PTD related leukemias.

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“…C) heterodimerize through their FYRN and FYRC interaction domains, which have been roughly mapped by two other groups. Yokoyama et al 15 identified two regions within the MLL protein, encompassing the amino acids 1256-2257 (N-terminal domain) and 3610-3745 (C-terminal domain), while Hsieh et al 16 defined regions spanning from amino acids 1978-2161 (N-terminal domain) and 3659-3972 (C-terminal domain). The defined interaction domains included the 40-90-amino-acids-long FYR regions rich in phenylalanine (F) and tyrosine (Y) residues.…”

Section: Introductionmentioning

confidence: 99%

“…13 The AF4-MLL fusion protein is a bona fide substrate for Taspase1, 14 similar to the prototypic MLL protein. 15,16 The resulting protein fragments (AF4-MLL . N and MLL .…”

Section: Introductionmentioning

confidence: 99%

The heterodimerization domains of MLL—FYRN and FYRC—are potential target structures in t(4;11) leukemia

et al. 2011

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The chromosomal translocation t(4;11)(q21;q23) is a frequent genetic aberration of the mixed lineage leukemia (MLL) gene, predominantly associated with high-risk acute lymphoblastic leukemia (ALL) in pediatric patients. Previous studies demonstrated that mice transplanted with hematopoietic cells expressing the AF4-MLL fusion protein develop proB ALL. The AF4-MLL oncoprotein becomes activated by Taspase1-mediated hydrolysis, which subsequently leads to a heterodimer of the cleavage products AF4-MLL . N and MLL . C. This proteinprotein interaction is due to the FYRN and FYRC interaction domains present in both protein fragments. Heterodimerization subsequently induces high-molecular-weight protein complex formation that is protected against SIAH1/2-mediated polyubiquitinylation. Here, we attempted to selectively block this initial heterodimerization step, aiming to prevent the oncogenic activation of the AF4-MLL multiprotein complex. The minimal interaction interface was experimentally defined first in a bacterial two-hybrid system, and then in mammalian cells by using a biosensor assay. Expression of the FYRC domain, or smaller portions thereof, resulted in the inhibition of heterodimer formation, and blocked AF4-MLL multiprotein complex formation with subsequent destruction of the AF4-MLL oncoprotein. Thus, it is in principle possible to specifically target the AF4-MLL protein. This knowledge can now be exploited to design inhibitory decoys in order to destroy the AF4-MLL oncoprotein.

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Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties

Cited by 150 publications

References 45 publications

MLL: How complex does it get?

MLL: How complex does it get?

Disordered epigenetic regulation in MLL-related leukemia

The heterodimerization domains of MLL—FYRN and FYRC—are potential target structures in t(4;11) leukemia

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