Definitive Hematopoiesis Requires the Mixed-Lineage Leukemia Gene

Ernst, Patricia; Fisher, Jill K.; Avery, William; Wade, Stacey; Foy, Daniel S.; Korsmeyer, Stanley J.

doi:10.1016/s1534-5807(04)00061-9

Cited by 238 publications

(187 citation statements)

References 38 publications

Supporting

Mentioning

176

Contrasting

Unclassified

Order By: Relevance

“…9,10 Wild-type MLL functions as an epigenetic regulator of transcription through histone methyltransferase activity, 32 and is essential for normal hematopoiesis. 7 Specifically, wild-type MLL methylates histone 3 at lysine 4 (H3K4), which embodies an evolutionary conserved histone mark associated with primed gene activation. Reinsuring activated transcription, H3K4 methylation induces an open or active chromatin state, and protects associated loci against DNA methylation at gene promoters to prevent associated genes from transcriptional silencing.…”

Section: Discussionmentioning

confidence: 99%

“…The most common MLL translocation among infant ALL patients, occurring in about 50% of the cases, is t(4;11) generating the fusion product MLL-AF4 (refs.1,5) as well as, in most instances, the reciprocal fusion product AF4-MLL. 6 Given the importance of the MLL gene in regulating transcription during definitive hematopoiesis, 7,8 interruptions of MLL lead to abnormal gene expression patterns that presumably favor leukemia development. 9,10 These unique gene expression profiles are to some extent mediated by leukemia-specific histone modifications, such as histone 3 lysine 79 dimethylation (H3K79me2), established via recruitment of DOT1L by MLL fusion partners.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Connectivity mapping identifies HDAC inhibitors for the treatment of t(4;11)-positive infant acute lymphoblastic leukemia

et al. 2011

View full text Add to dashboard Cite

MLL-rearranged infant acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia characterized by a unique geneexpression profile. We uncovered that the activation of particular (proto-onco)genes is mediated by promoter hypomethylation. In search for therapeutic agents capable of targeting these potential cancer-promoting genes, we applied connectivity mapping on a gene expression signature based on the genes most significantly hypomethylated in t(4;11)-positive infant ALL as compared with healthy bone marrows. This analysis revealed histone deacetylase (HDAC) inhibitors as suitable candidates to reverse the unfavorable gene signature. We show that HDAC inhibitors effectively induce leukemic cell death in t(4;11)-positive primary infant ALL cells, accompanied by downregulation of MYC, SET, RUNX1, RAN as well as the MLL-AF4 fusion product. Furthermore, DNA methylation was restored after HDAC inhibitor exposure. Our data underlines the essential role for epigenetic de-regulation in MLL-rearranged ALL. Furthermore, we show, for the first time, that connectivity mapping can indirectly be applied on DNA methylation patterns, providing a rationale for HDAC inhibition in t(4;11)-positive leukemias. Given the presented potential of HDAC inhibitors to target important proto-oncogenes including the leukemia-specific MLL fusion in vitro, these agents should urgently be tested in in vivo models and subsequent clinical trials.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Connectivity mapping identifies HDAC inhibitors for the treatment of t(4;11)-positive infant acute lymphoblastic leukemia

et al. 2011

View full text Add to dashboard Cite

show abstract

“…205 When Bad associates with Bcl-2 or Bcl-X L , it promotes apoptosis by preventing Bcl-2 or Bcl-X L from interacting with Bax. [206][207][208][209][210][211][212] Bad is phosphorylated in most AML specimens suggesting that inhibition of Bad phosphorylation may be therapeutically important in AML. 213 In contrast, the antiapoptotic Mcl-1 protein is not reported to interact with Bad.…”

Section: Overview Of Jak/stat Pathwaymentioning

confidence: 99%

“…210 Bcl-X L can prevent the formation of Bax:Bax homodimers. 212 Hence the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR, Jak/STAT and JNK pathways regulate many molecules involved in prevention of apoptosis. Dysregulation of these pathways may contribute to leukemia.…”

Section: Overview Of Jak/stat Pathwaymentioning

confidence: 99%

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

et al. 2008

View full text Add to dashboard Cite

Mutations and chromosomal translocations occur in leukemic cells that result in elevated expression or constitutive activation of various growth factor receptors and downstream kinases. The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are often activated by mutations in upstream genes. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are regulated by upstream Ras that is frequently mutated in human cancer. Recently, it has been observed that the FLT-3 and Jak kinases and the phosphatase and tensin homologue deleted on chromosome 10 ( PTEN) phosphatase are also frequently mutated or their expression is altered in certain hematopoietic neoplasms. Many of the events elicited by the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways have direct effects on survival pathways. Aberrant regulation of the survival pathways can contribute to uncontrolled cell growth and lead to leukemia. In this review, we describe the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT signaling cascades and summarize recent data regarding the regulation and mutation status of these pathways and their involvement in leukemia

show abstract

“…Mlldeficient mice exhibit defective yolk sac and fetal liver hematopoiesis [8,9], and Hox gene expression was initiated but not maintained in these mice [10]. Animals carrying a single normal Mll allele are phenotypically abnormal, with mild anemia and thrombocytopenia [8,9], and studies using chimeric mice reconstituted with Mll deficient or hemizygous embryonic stem cells suggest that Mll is essential for hematopoietic stem cell (HSC) development itself, or for the transition of HSC to multipotent progenitors [11].…”

Section: Mll and Its Role In Normal Hematopoiesismentioning

confidence: 99%

Disordered epigenetic regulation in MLL-related leukemia

et al. 2012

View full text Add to dashboard Cite

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.

show abstract

Definitive Hematopoiesis Requires the Mixed-Lineage Leukemia Gene

Cited by 238 publications

References 38 publications

Connectivity mapping identifies HDAC inhibitors for the treatment of t(4;11)-positive infant acute lymphoblastic leukemia

Connectivity mapping identifies HDAC inhibitors for the treatment of t(4;11)-positive infant acute lymphoblastic leukemia

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

Disordered epigenetic regulation in MLL-related leukemia

Contact Info

Product

Resources

About