MLL/AF-4 leukemic cells recruit new blood vessels but do not incorporate into capillaries in culture or in a NOD/SCID xenograft model

Hu, Zhongbo; Xm, Li; Ml, Jorgensen; Wb, Slayton

doi:10.1038/leu.2008.345

Cited by 4 publications

(4 citation statements)

References 10 publications

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“…Conversely, MLL-FPs alone can directly cause aggressive acute leukemias in mouse model systems as well as in Xenograft assays [12,126,127,128,129,130,131,132,133,134,135,136,137,138,139]. In human patients, the prognosis for leukemias containing MLL-FPs varies somewhat with the different fusion partners but is generally quite poor ([140,141], reviewed in [122] and in [142]).…”

Section: Mll and Leukemiamentioning

confidence: 99%

“…Also, MLL-FPs alone are often capable of rapidly producing acute leukemias in mice [12,126,127,128,129,130,131,132,133,134,135,136,137,138,139]. This indicates that the expression of MLL-FPs is sufficient for the promotion of leukemogenesis, likely through the epigenetic activation of key master regulatory factors that set up gene expression networks responsible for cell growth and proliferation.…”

Section: Mll and Leukemiamentioning

confidence: 99%

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Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis

Ballabio

Milne

2012

Cancers

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Epigenetics is often defined as the study of heritable changes in gene expression or chromosome stability that don’t alter the underlying DNA sequence. Epigenetic changes are established through multiple mechanisms that include DNA methylation, non-coding RNAs and the covalent modification of specific residues on histone proteins. It is becoming clear not only that aberrant epigenetic changes are common in many human diseases such as leukemia, but that these changes by their very nature are malleable, and thus are amenable to treatment. Epigenetic based therapies have so far focused on the use of histone deacetylase (HDAC) inhibitors and DNA methyltransferase inhibitors, which tend to have more general and widespread effects on gene regulation in the cell. However, if a unique molecular pathway can be identified, diseases caused by epigenetic mechanisms are excellent candidates for the development of more targeted therapies that focus on specific gene targets, individual binding domains, or specific enzymatic activities. Designing effective targeted therapies depends on a clear understanding of the role of epigenetic mutations during disease progression. The Mixed Lineage Leukemia (MLL) protein is an example of a developmentally important protein that controls the epigenetic activation of gene targets in part by methylating histone 3 on lysine 4. MLL is required for normal development, but is also mutated in a subset of aggressive human leukemias and thus provides a useful model for studying the link between epigenetic cell memory and human disease. The most common MLL mutations are chromosome translocations that fuse the MLL gene in frame with partner genes creating novel fusion proteins. In this review, we summarize recent work that argues MLL fusion proteins could function through a single molecular pathway, but we also highlight important data that suggests instead that multiple independent mechanisms underlie MLL mediated leukemogenesis.

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Section: Mll and Leukemiamentioning

confidence: 99%

Section: Mll and Leukemiamentioning

confidence: 99%

Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis

Ballabio

Milne

2012

Cancers

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“…First, MLL/AF4-positive ALL cells strongly recruit new blood vessels. 3 Second, MLL/AF4-positive ALL escapes from TNF-␣-mediated apoptosis by upregulating the expression of S100A6, which is a 10.5-kDa Ca 2ϩ -binding protein belonging to the S100 protein family that has been reported to interact with and alter the conformation of p53. [4][5][6][7][8][9][10][11] Up-regulation of S100A6 expression in MLL/AF4-positive ALL inhibits p53 acetylation followed by inhibition of upregulation of the caspase 8-caspase 3 apoptotic pathway in the presence of TNF-␣.…”

Section: Introductionmentioning

confidence: 99%

AAV8 vector expressing IL24 efficiently suppresses tumor growth mediated by specific mechanisms in MLL/AF4-positive ALL model mice

Tamai

Miyake

Yamaguchi³

et al. 2012

Blood

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Mixed-lineage leukemia (MLL)/AF4-positive acute lymphoblastic leukemia (ALL) is a common type of leukemia in infants, which is associated with a high relapse rate and poor prognosis. IL24 selectively induces apoptosis in cancer cells and exerts immunomodulatory and antiangiogenic effects. We examined the effects of adeno-associated virus type 8 (AAV8) vector-mediated muscle-directed systemic gene therapy in MLL/AF4-positive ALL using IL24. In a series of in vitro studies, we examined the effects of AAV8-IL24-transduced C2C12 cell-conditioned medium. We also examined the effects of AAV8-IL24 in MLL/AF4 transgenic mice. The results revealed the effects of AAV8-IL24 in MLL/AF4-positive ALL both in vitro and in vivo. With regard to the mechanism of therapy using AAV8-IL24 in MLL/ AF4-positive ALL, we demonstrated the antiangiogenicity and effects on the ER stress pathway and unreported pathways through inhibition of S100A6 and HOXA9, which is specific to MLL/AF4-positive ALL. Inhibition of S100A6 by IL24 was dependent on TNF-␣ and induced acetylation of p53 followed by activation of the caspase 8-caspase 3 apoptotic pathway. Inhibition of HOXA9 by IL24, which was independent of TNF-␣, induced MEIS1 activation followed by activation of the caspase 8-caspase 3 apoptotic pathway. Thus, gene therapy using AAV8-IL24 is a promising treatment for MLL/AF4-positive ALL. IntroductionRearrangements of the mixed-lineage leukemia (MLL) gene located at 11q23 are common chromosomal abnormalities associated with acute leukemia, especially infant leukemia and secondary leukemia after treatment with DNA topoisomerase II inhibitors. In addition, 11q23/MLL abnormalities are now widely recognized as important prognostic factors in acute leukemia. More than 70 chromosomal partners of 11q23 have been identified to date, at least 50 of which have been cloned and characterized at the molecular level. 1 The prognosis of leukemia patients with MLL rearrangement varies widely depending on the partner gene, leukemia cell lineage, age of the patient, and treatment administered. 2 The most prevalent MLL rearrangement in acute lymphoblastic leukemia (ALL) generates the MLL/AF4 fusion gene because of a t(4;11)(q21;q23) chromosomal translocation. Despite recent improvements in the overall treatment outcome for ALL patients, including allogeneic HSCT (allo-HSCT), MLL/AF4-positive ALL is still associated with a poor prognosis. 2 The following are 3 factors that may be related to the poor prognosis of MLL/AF4-positive ALL. First, MLL/AF4-positive ALL cells strongly recruit new blood vessels. 3 Second, MLL/AF4-positive ALL escapes from TNF-␣-mediated apoptosis by upregulating the expression of S100A6, which is a 10.5-kDa Ca 2ϩ -binding protein belonging to the S100 protein family that has been reported to interact with and alter the conformation of p53. [4][5][6][7][8][9][10][11] Up-regulation of S100A6 expression in MLL/AF4-positive ALL inhibits p53 acetylation followed by inhibition of upregulation of the caspase 8-caspase 3 apoptotic pathway in the ...

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“…45 Over the last decade elegant work published by several groups has shown that expression of several different MLL-fusions alone is sufficient to drive leukemic transformation irrespective of the fusion partner, and without additional cooperating mutations through the induction of widespread epigenetic dysregulation, again suggesting a common mechanism for MLL-fusion mediated leukemogenesis. [46][47][48][49][50][51] Analyses of gene expression patterns from patient leukemic blasts expressing several different MLL-fusions, have shown that MLL fusion proteins preferentially upregulate and maintain expression of a specific subset of wild-type MLL gene targets, most notably MEIS1 and the HOXA cluster, thus disrupting the normal progression of hematopoietic gene expression. Taken together these findings demonstrated overall that MLL-fusion proteins likely function through a common underlying mechanism influencing gene expression through aberrant recruitment of epigenetic machinery to lineage-specific developmental genes leading to their constitutive expression thus driving leukemogenesis.…”

Section: Mll-fusion Protein Signaling and Functional Dependence On Thmentioning

confidence: 99%

Characterization of a more clinically relevant human leukemia xenograft model to examine perturbation of MET/SAM metabolism as a novel therapeutic paradigm for MLL-R leukemia in vivo.

Barve¹

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Acute myeloid leukemia (AML), is a heterogeneous clonal disorder characterized by an accumulation of malignant myeloid progenitors in the bone marrow (BM), hindering normal hematopoiesis. AML exhibits dramatic heterogeneity in terms of cytogenetics, morphology, and chemotherapeutic sensitivity. Therefore, the investigation of novel, efficacious AML therapeutics will require advanced preclinical in vivo model systems, capable of recapitulating patient specific disease heterogeneity, and induction chemotherapy outcomes. A major focus and eventual outcome of this work was the establishment and development of a more clinically relevant mouse xenograft model of patient AML, that efficiently harbors patient derived xenografts (PDXs), and unlike more v prevalent SCID models can tolerate more clinically relevant doses of DNA damaging induction chemotherapy. We examined the functional utility of our newly established, advanced AML PDX model to confirm our in vitro findings that perturbation of methionine (Met) / S-adenosylmethionine (SAM) metabolism is uniquely cytotoxic to MLLrearranged (MLL-R) leukemic cells, in vivo. We demonstrate here that perturbation of Met/SAM metabolism decreases intracellular methylation potential, alters global histone methylation dynamics, impairs the expression and function of the H3K79 methyltransferase DOT1L, and induces apoptosis in MLL-R leukemic cells. We show a significant extension in the survival of mice harboring aggressive patient MLL-R leukemias, when treated with a pharmacologic inhibitor of Met/SAM metabolism and induction therapy, as compared to induction alone. The work featured in this dissertation establishes a novel chemotherapy tolerant AML xenograft model, demonstrates its translational utility, and supports the continued investigation of targeted inhibition of Met/SAM

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MLL/AF-4 leukemic cells recruit new blood vessels but do not incorporate into capillaries in culture or in a NOD/SCID xenograft model

Cited by 4 publications

References 10 publications

Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis

Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis

AAV8 vector expressing IL24 efficiently suppresses tumor growth mediated by specific mechanisms in MLL/AF4-positive ALL model mice

Characterization of a more clinically relevant human leukemia xenograft model to examine perturbation of MET/SAM metabolism as a novel therapeutic paradigm for MLL-R leukemia in vivo.

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