myeloid lymphoid leukemia protein

Summary

Summary: Myeloid-lymphoid leukemia protein is a transcription factor that maintains high levels of HOMEOTIC GENE expression during development. The GENE for myeloid-lymphoid leukemia protein is commonly disrupted in LEUKEMIA and combines with over 40 partner genes to form FUSION ONCOGENE PROTEINS.

Top Publications

  1. Popovic R, Riesbeck L, Velu C, Chaubey A, Zhang J, Achille N, et al. Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. Blood. 2009;113:3314-22 pubmed publisher
    ..Our results suggest a mechanism whereby increased expression of mir-196b by MLL fusion proteins significantly contributes to leukemia development. ..
  2. Liu H, Cheng E, Hsieh J. MLL fusions: pathways to leukemia. Cancer Biol Ther. 2009;8:1204-11 pubmed
    ..Here, we summarize the critical biological and pathological activities of MLL and MLL fusions, and discuss available models and potential therapeutic targets of MLL associated leukemias...
  3. Bueno C, Catalina P, Melen G, Montes R, Sanchez L, Ligero G, et al. Etoposide induces MLL rearrangements and other chromosomal abnormalities in human embryonic stem cells. Carcinogenesis. 2009;30:1628-37 pubmed publisher
  4. Chang P, Hom R, Musselman C, Zhu L, Kuo A, Gozani O, et al. Binding of the MLL PHD3 finger to histone H3K4me3 is required for MLL-dependent gene transcription. J Mol Biol. 2010;400:137-44 pubmed publisher
    ..Furthermore, these findings reveal that MLL not only "writes" the H3K4me3 mark but also binds the mark, and this binding is required for the transcriptional maintenance functions of MLL. ..
  5. Meyer C, Kowarz E, Hofmann J, Renneville A, Zuna J, Trka J, et al. New insights to the MLL recombinome of acute leukemias. Leukemia. 2009;23:1490-9 pubmed publisher
    ..Moreover, we describe for the first time the genetic network of reciprocal MLL gene fusions deriving from complex rearrangements...
  6. Hom R, Chang P, Roy S, Musselman C, Glass K, Selezneva A, et al. Molecular mechanism of MLL PHD3 and RNA recognition by the Cyp33 RRM domain. J Mol Biol. 2010;400:145-54 pubmed publisher
    ..Together, these in vitro and in vivo data provide insight into the multiple functions of Cyp33 RRM and suggest a Cyp33-dependent mechanism for regulating the transcriptional activity of MLL. ..
  7. LIEDTKE M, Cleary M. Therapeutic targeting of MLL. Blood. 2009;113:6061-8 pubmed publisher
    ..These advances in our understanding of MLL-related leukemogenesis provide a foundation for ongoing and future efforts to develop novel therapeutic strategies that will hopefully result in better treatment outcomes. ..
  8. Jin S, Zhao H, Yi Y, Nakata Y, Kalota A, Gewirtz A. c-Myb binds MLL through menin in human leukemia cells and is an important driver of MLL-associated leukemogenesis. J Clin Invest. 2010;120:593-606 pubmed publisher
  9. Wang P, Lin C, Smith E, Guo H, Sanderson B, Wu M, et al. Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. Mol Cell Biol. 2009;29:6074-85 pubmed publisher
    ..Together these data provide insight into the redundancy and specialization of COMPASS-like complexes in mammals and provide evidence for a possible role for Mll1-mediated H3K4 methylation in the regulation of transcriptional initiation. ..

More Information

Publications62

  1. Tyagi S, Herr W. E2F1 mediates DNA damage and apoptosis through HCF-1 and the MLL family of histone methyltransferases. EMBO J. 2009;28:3185-95 pubmed publisher
    ..Indeed, sequence changes in the E2F1 HCF-1-binding site can modulate both up and down the ability of E2F1 to induce apoptosis indicating that HCF-1 association with E2F1 is a regulator of E2F1-induced apoptosis. ..
  2. Caslini C, Connelly J, Serna A, Broccoli D, Hess J. MLL associates with telomeres and regulates telomeric repeat-containing RNA transcription. Mol Cell Biol. 2009;29:4519-26 pubmed publisher
  3. Britton S, Frit P, Biard D, Salles B, Calsou P. ARTEMIS nuclease facilitates apoptotic chromatin cleavage. Cancer Res. 2009;69:8120-6 pubmed publisher
    ..These results show a facilitating role for ARTEMIS at least in early, site-specific chromosome breakage during apoptosis. ..
  4. Bach C, Slany R. Molecular pathology of mixed-lineage leukemia. Future Oncol. 2009;5:1271-81 pubmed publisher
    ..Additionally, the roles of some target genes, as well as co-factors of mixed-lineage leukemia fusion proteins, are described with an emphasis on recent advances potentially uncovering novel therapeutic targets. ..
  5. Kato N, Kitamura T. [Cytogenetic abnormalities and gene mutations in myeloid leukemia]. Nihon Rinsho. 2009;67:1875-9 pubmed
    ..In this article, we summarize some typical chromosomal abnormalities or gene mutations associated with myeloid leukemia on the basis of this hypothesis. ..
  6. Bardini M, Spinelli R, Bungaro S, Mangano E, Corral L, Cifola I, et al. DNA copy-number abnormalities do not occur in infant ALL with t(4;11)/MLL-AF4. Leukemia. 2010;24:169-76 pubmed publisher
    ..It can be argued that the MLL rearrangement as a first hit, rather than inducing the acquisition of additional genetic lesions, has a major role to drive and hasten the onset of leukemia. ..
  7. Cierpicki T, Risner L, Grembecka J, Lukasik S, Popovic R, Omonkowska M, et al. Structure of the MLL CXXC domain-DNA complex and its functional role in MLL-AF9 leukemia. Nat Struct Mol Biol. 2010;17:62-8 pubmed publisher
    ..They also provide support for viewing this interaction as a potential target for therapeutic intervention. ..
  8. Saito H, Otsubo K, Kakimoto A, Komatsu N, Ohsaka A. Emergence of two unrelated clones in acute myeloid leukemia with MLL-SEPT9 fusion transcript. Cancer Genet Cytogenet. 2010;201:111-5 pubmed publisher
    ..Thus, the karyotype was defined as 46,XY,t(11;17)(q23;q25)/46,XY,t(1;6)(p36.3;q23). Our case represents an additional MLL-SEPT9-positive AML that was considered to be related to therapy. ..
  9. Brès V, Yoshida T, Pickle L, Jones K. SKIP interacts with c-Myc and Menin to promote HIV-1 Tat transactivation. Mol Cell. 2009;36:75-87 pubmed publisher
    ..Thus, SKIP acts with c-Myc and Menin to promote HIV-1 Tat:P-TEFb transcription at an elongation step that is bypassed under stress. ..
  10. Damm F, Heuser M, Morgan M, Yun H, Grosshennig A, Göhring G, et al. Single nucleotide polymorphism in the mutational hotspot of WT1 predicts a favorable outcome in patients with cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2010;28:578-85 pubmed publisher
    ..WT1 SNP rs16754 may be a novel independent favorable-risk marker in CN-AML patients that might improve risk and treatment stratification. ..
  11. Schafer E, Irizarry R, Negi S, McIntyre E, Small D, Figueroa M, et al. Promoter hypermethylation in MLL-r infant acute lymphoblastic leukemia: biology and therapeutic targeting. Blood. 2010;115:4798-809 pubmed publisher
    ..Methylation-specific PCR (MSP) confirmed promoter hypermethylation at baseline, and a relative decrease in methylation after treatment. DNMTi may represent a novel molecularly targeted therapy for MLL-r infant ALL. ..
  12. Yokoyama A, Lin M, Naresh A, Kitabayashi I, Cleary M. A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. Cancer Cell. 2010;17:198-212 pubmed publisher
    ..Thus, AEP recruitment is an integral part of both physiological and pathological MLL-dependent transcriptional pathways. Bypass of its normal recruitment mechanisms is the strategy most frequently used by MLL oncoproteins. ..
  13. Kohler C, Aichinger E. Antagonizing Polycomb group-mediated gene repression by chromatin remodelers. Epigenetics. 2010;5:20-3 pubmed
    ..Here we will discuss the implications of these findings that point towards an evolutionary conservation of PcG/trxG mediated gene regulation in higher eukaryotes. ..
  14. Aljurf M, Nassar A, Saleh A, Almhareb F, Alzahrani H, Walter C, et al. Maternal acute lymphoctic leukemia with rearrangement of the mixed lineage leukemia gene occurring during pregnancy. Hematol Oncol Stem Cell Ther. 2009;2:399-402 pubmed
    ..We believe that the association of MLL gene rearrangement with maternal leukemia is biologically plausible and this observation needs to be validated in a larger cohort of pregnancy-associated maternal leukemia cases. ..
  15. Burmeister T, Gökbuget N, Schwartz S, Fischer L, Hubert D, Sindram A, et al. Clinical features and prognostic implications of TCF3-PBX1 and ETV6-RUNX1 in adult acute lymphoblastic leukemia. Haematologica. 2010;95:241-6 pubmed publisher
    ..Both groups of patients are characterized by distinct clinicobiological features which facilitate their diagnostic identification. ..
  16. LIEDTKE M, Ayton P, Somervaille T, Smith K, Cleary M. Self-association mediated by the Ras association 1 domain of AF6 activates the oncogenic potential of MLL-AF6. Blood. 2010;116:63-70 pubmed publisher
  17. Pieters R. Infant acute lymphoblastic leukemia: Lessons learned and future directions. Curr Hematol Malig Rep. 2009;4:167-74 pubmed publisher
    ..New genetic and epigenetic insights into the biology of MLL-rearranged ALL suggest new possibilities for therapies. ..
  18. Cerveira N, Santos J, Bizarro S, Costa V, Ribeiro F, Lisboa S, et al. Both SEPT2 and MLL are down-regulated in MLL-SEPT2 therapy-related myeloid neoplasia. BMC Cancer. 2009;9:147 pubmed publisher
    ..023) We found a significant down-regulation of both SEPT2 and MLL in MLL-SEPT2 myeloid neoplasias. In addition, we also found that MLL is under-expressed in AML patients with MLL fusions other than MLL-SEPT2. ..
  19. Ansari K, Hussain I, Das H, Mandal S. Overexpression of human histone methylase MLL1 upon exposure to a food contaminant mycotoxin, deoxynivalenol. FEBS J. 2009;276:3299-307 pubmed publisher
    ..These results demonstrated that MLL1 gene expression is sensitive to toxic stress and Sp1 plays crucial roles in the stress-induced upregulation of MLL1. ..
  20. Milne T, Kim J, Wang G, Stadler S, Basrur V, Whitcomb S, et al. Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis. Mol Cell. 2010;38:853-63 pubmed publisher
    ..Since wild-type MLL1 and oncogenic MLL1 fusion proteins have overlapping yet distinct recruitment mechanisms, this creates a window of opportunity that could be exploited for the development of targeted therapies. ..
  21. Kaltenbach S, Soler G, Barin C, Gervais C, Bernard O, Penard Lacronique V, et al. NUP98-MLL fusion in human acute myeloblastic leukemia. Blood. 2010;116:2332-5 pubmed publisher
    ..As expected, low levels of HOXA gene expression were observed in the patients' samples. This fusion protein is predicted to participate in cellular transformation by activating MLL targets other than HOXA genes. ..
  22. Mills A. Throwing the cancer switch: reciprocal roles of polycomb and trithorax proteins. Nat Rev Cancer. 2010;10:669-82 pubmed publisher
    ..Recent work highlights the dynamic interplay between these opposing classes of proteins, providing new avenues for understanding how these epigenetic regulators function in tumorigenesis. ..
  23. Gan T, Jude C, Zaffuto K, Ernst P. Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis. Leukemia. 2010;24:1732-41 pubmed publisher
    ..Collectively, these data support the conclusion that Mll has an essential role in sustaining postnatal haematopoiesis. ..
  24. Lim D, Huang Y, Swigut T, Mirick A, Garcia Verdugo J, Wysocka J, et al. Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells. Nature. 2009;458:529-33 pubmed publisher
    ..These data support a model in which Mll1 is required to resolve key silenced bivalent loci in postnatal neural precursors to the actively transcribed state for the induction of neurogenesis, but not for gliogenesis. ..
  25. van der Velden V, Corral L, Valsecchi M, Jansen M, De Lorenzo P, Cazzaniga G, et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia. 2009;23:1073-9 pubmed publisher
    ..These data indicate that MRD diagnostics has added value for recognition of risk groups in infant ALL and that MRD diagnostics can be used for treatment intervention in infant ALL as well...
  26. Zamecnikova A, Al Bahar S. Simultaneous occurrence of MLL and RARA rearrangements in a pediatric acute lymphoblastic leukemia patient. Pediatr Blood Cancer. 2009;52:671-4 pubmed publisher
    ..Concurrent translocations of two specific oncogenes MLL and RARA with a new partner breakpoint on 5q31 have not been previously described. ..
  27. Ng M, Ng R, Kong C, Jin D, Chan L. Activation of Ras-dependent Elk-1 activity by MLL-AF4 family fusion oncoproteins. Exp Hematol. 2010;38:481-8 pubmed publisher
  28. Chen S, Yang C, Hung I, Jaing T, Shih L, Tsai M. Clinical features, molecular diagnosis, and treatment outcome of infants with leukemia in Taiwan. Pediatr Blood Cancer. 2010;55:1264-71 pubmed publisher
    ..The molecular assessments and prognostic factors of infant leukemia in Taiwan mirror those in developed Western countries. Continued molecular investigations and development of more effective therapies are needed. ..
  29. Valencia A, Cervera J, Such E, Ibañez M, Barragan E, Fuster O, et al. A new reliable fluorescence in situ hybridization method for identifying multiple specific cytogenetic abnormalities in acute myeloid leukemia. Leuk Lymphoma. 2010;51:680-5 pubmed publisher
    ..It is also capable of reallocating cases without metaphases or with non-evaluable chromosomes in the appropriate cytogenetic risk group. ..
  30. Stevens S, Meers L, Albrechts J, Mebis Verhees K, Bos G, Engelen J, et al. A translocation in acute lymphoblastic leukemia that cytogenetically mimics the recurrent MLL-AFF1 translocation and fuses SEPT11 to MLL. Cancer Genet Cytogenet. 2010;201:48-51 pubmed publisher
    ..Their putative oncogenic role may be related to forced MLL dimerization by the septin coiled coil and GTP-binding domains, which could convert MLL to an oncogene. ..
  31. Karatas H, Townsend E, Bernard D, Dou Y, Wang S. Analysis of the binding of mixed lineage leukemia 1 (MLL1) and histone 3 peptides to WD repeat domain 5 (WDR5) for the design of inhibitors of the MLL1-WDR5 interaction. J Med Chem. 2010;53:5179-85 pubmed publisher
    ..Our study provides a concrete basis for the design of potent peptidomimetics and nonpeptidic compounds to inhibit MLL1 activity by targeting the MLL1 and WDR5 interaction. ..
  32. Balgobind B, Hollink I, Reinhardt D, van Wering E, De Graaf S, Baruchel A, et al. Low frequency of MLL-partial tandem duplications in paediatric acute myeloid leukaemia using MLPA as a novel DNA screenings technique. Eur J Cancer. 2010;46:1892-9 pubmed publisher
    ..Larger prospective studies are needed to further define the prognostic relevance of MLL-PTD in paediatric AML. ..
  33. Doubek M, Palasek I, Pospisil Z, Borsky M, Klabusay M, Brychtova Y, et al. Detection and treatment of molecular relapse in acute myeloid leukemia with RUNX1 (AML1), CBFB, or MLL gene translocations: frequent quantitative monitoring of molecular markers in different compartments and correlation with WT1 gene expression. Exp Hematol. 2009;37:659-72 pubmed publisher
    ..Frequent quantitative monitoring of fusion transcripts is useful for reliably predicting hematological relapse in AML patients. Treatment for molecular relapse of AML can be successful. ..
  34. Lotterman C, Kent O, Mendell J. Functional integration of microRNAs into oncogenic and tumor suppressor pathways. Cell Cycle. 2008;7:2493-9 pubmed
    ..Gain- and loss-of-function of these factors in cancer cells contributes to miRNA dysregulation, directly influencing neoplastic phenotypes including cellular proliferation and apoptosis. ..
  35. Brüschweiler S, Schanda P, Kloiber K, Brutscher B, Kontaxis G, Konrat R, et al. Direct observation of the dynamic process underlying allosteric signal transmission. J Am Chem Soc. 2009;131:3063-8 pubmed publisher
    ..Our dynamic NMR data reveal that an evolutionarily conserved network of hydrophobic amino acids constitutes the pathway through which information is transmitted. ..
  36. Robert I, Aussems M, Keutgens A, Zhang X, Hennuy B, Viatour P, et al. Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-kappaB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes. Oncogene. 2009;28:1626-38 pubmed publisher
  37. Nakayama T, Yamashita M. Critical role of the Polycomb and Trithorax complexes in the maintenance of CD4 T cell memory. Semin Immunol. 2009;21:78-83 pubmed publisher
    ..Therefore, in memory CD4 T cells, PcG and TrxG genes appear to control distinct processes in a distinct manner, which indicates a novel regulatory feature of the PcG/TrxG genes. ..
  38. Horiguchi K, Yamada M, Satoh T, Hashimoto K, Hirato J, Tosaka M, et al. Transcriptional activation of the mixed lineage leukemia-p27Kip1 pathway by a somatostatin analogue. Clin Cancer Res. 2009;15:2620-9 pubmed publisher
  39. Zuber J, Radtke I, Pardee T, Zhao Z, Rappaport A, Luo W, et al. Mouse models of human AML accurately predict chemotherapy response. Genes Dev. 2009;23:877-89 pubmed publisher
  40. Cao F, Li X, Hiew S, Brady H, Liu Y, Dou Y. Dicer independent small RNAs associate with telomeric heterochromatin. RNA. 2009;15:1274-81 pubmed publisher
    ..These results support that tel-sRNAs are heterochromatin associated pi-like small RNAs. ..
  41. Rayeroux K, Campbell L. Gene amplification in myeloid leukemias elucidated by fluorescence in situ hybridization. Cancer Genet Cytogenet. 2009;193:44-53 pubmed publisher
    ..1, 15q26.1 approximately q26.3, and 17q12. We also identified one case where two different chromosomal regions were simultaneously amplified in the same cell line. ..
  42. Fu J, Hsu C, Shih L. MLL/AF10(OM-LZ)-immortalized cells expressed cytokines and induced host cell proliferation in a mouse bone marrow transplantation model. Int J Cancer. 2010;126:1621-9 pubmed publisher
    ..Our results showed that the MLL/AF10(OM-LZ)-immortalized cells could induce host cell proliferation in the transplanted mice, probably through stimulation by CSFs or cytokines produced by the donor cells. ..
  43. Ikawa Y, Sugimoto N, Koizumi S, Yachie A, Saikawa Y. Dense methylation of types 1 and 2 regulatory regions of the CD10 gene promoter in infant acute lymphoblastic leukemia with MLL/AF4 fusion gene. J Pediatr Hematol Oncol. 2010;32:4-10 pubmed publisher
    ..Structural evidence of dense methylation in the CD10 gene promoter suggested that methylated transcription factor binding sites contribute to CD10 silencing as an epigenetic mechanism. ..
  44. Blobel G, Kadauke S, Wang E, Lau A, Zuber J, Chou M, et al. A reconfigured pattern of MLL occupancy within mitotic chromatin promotes rapid transcriptional reactivation following mitotic exit. Mol Cell. 2009;36:970-83 pubmed publisher
    ..These findings implicate mitotic bookmarking as a component of Trithorax-based gene regulation, which may facilitate inheritance of active gene expression states during cell division. ..
  45. Balgobind B, Raimondi S, Harbott J, Zimmermann M, Alonzo T, Auvrignon A, et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood. 2009;114:2489-96 pubmed publisher
    ..Screening for these translocation partners is needed for accurate treatment stratification at diagnosis. ..
  46. Cerveira N, Santos J, Teixeira M. Structural and expression changes of septins in myeloid neoplasia. Crit Rev Oncog. 2009;15:91-115 pubmed
  47. Ansari K, Mandal S. Mixed lineage leukemia: roles in gene expression, hormone signaling and mRNA processing. FEBS J. 2010;277:1790-804 pubmed publisher
    ..In this minireview, we summarize recent advances in understanding the roles of MLLs in gene regulation and hormone signaling and highlight their potential roles in mRNA processing. ..
  48. Muntean A, Tan J, Sitwala K, Huang Y, Bronstein J, Connelly J, et al. The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis. Cancer Cell. 2010;17:609-21 pubmed publisher
    ..Deletions of MLL that abolish interactions with PAFc also eliminate MLL-AF9 mediated immortalization indicating an essential function for this interaction in leukemogenesis. ..
  49. Marschalek R. Mixed lineage leukemia: roles in human malignancies and potential therapy. FEBS J. 2010;277:1822-31 pubmed publisher
  50. Zatkova A, Merk S, Wendehack M, Bilban M, Muzik E, Muradyan A, et al. AML/MDS with 11q/MLL amplification show characteristic gene expression signature and interplay of DNA copy number changes. Genes Chromosomes Cancer. 2009;48:510-20 pubmed publisher
    ..Furthermore, we demonstrate that the gene expression signature can be used to discriminate AML/MDS with MLL amplification from several other types of AML. ..
  51. Kim S, Kim H, Kim S. [Clinical utility of fluorescence in-situ hybridization profile test in detecting genetic aberrations in acute leukemia]. Korean J Lab Med. 2009;29:371-8 pubmed publisher
    ..Our study supports the need to incorporate FISH profile test at initial work up in acute leukemia. ..
  52. Mishra B, Ansari K, Mandal S. Dynamic association of MLL1, H3K4 trimethylation with chromatin and Hox gene expression during the cell cycle. FEBS J. 2009;276:1629-40 pubmed publisher
    ..In conclusion, our studies demonstrate that MLL1 and H3K4 methylation have distinct dynamics during the cell cycle and play critical roles in the differential expression of Hox genes associated with cell cycle regulation. ..
  53. Kudo M, Saito Y, Sasaki T, Akasaki H, Yamaguchi Y, Uehara M, et al. Genetic variations in the HGPRT, ITPA, IMPDH1, IMPDH2, and GMPS genes in Japanese individuals. Drug Metab Pharmacokinet. 2009;24:557-64 pubmed
    ..620) and GMPS: IVS5-7T>C (0.153), 993A>G (Thr331Thr, 0.153)) were identified in 200 Japanese subjects. These data should provide useful information for thiopurine therapy in the Japanese and as well as other Asian populations. ..