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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Faithful modeling of mixed-lineage leukemia in murine cells has been difficult to achieve. We show that expression of MLL-AF9 in human CD34+ cells induces acute myeloid, lymphoid, or mixed-lineage leukemia in immunodeficient mice. Some leukemia stem cells (LSC) were multipotent and could be lineage directed by altering either the growth factors or the recipient strain of mouse, highlighting the importance of microenvironmental cues. Other LSC were strictly lineage committed, demonstrating the heterogeneity of the stem cell compartment in MLL disease. Targeting the Rac signaling pathway by pharmacologic or genetic means resulted in rapid and specific apoptosis of MLL-AF9 cells, suggesting that the Rac signaling pathway may be a valid therapeutic target in MLL-rearranged AML.
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PMID:Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. 1853 28

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene are associated with aggressive acute lymphoid and myeloid leukemias. These translocations are restricted to an 8.3-kb breakpoint region resulting in fusion of amino terminal MLL sequences in frame to 1 of more than 60 different translocation partners. The translocations consistently delete the plant homeodomain (PHD) fingers and more carboxyl terminal MLL sequences. The function of the PHD fingers is obscure and their specific role in transformation has not been explored. Here we show that inclusion of the PHD fingers in the MLL fusion protein MLL-AF9 blocked immortalization of hematopoietic progenitors. Inclusion of 2 or more PHD fingers reduced association with the Hoxa9 locus and suppressed Hoxa9 up-regulation in hematopoietic progenitors. These data provide an explanation for why MLL translocation breakpoints exclude the PHD fingers and suggest a possible role for these domains in regulating the function of wild-type MLL.
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PMID:The PHD fingers of MLL block MLL fusion protein-mediated transformation. 1879 27

MLL-AF9 (MA9) is a leukemia fusion gene formed upon translocation of the AF9 gene on chromosome 9 and the MLL gene on chromosome 11. MA9 is commonly found in acute myeloid leukemia (AML) and occasionally in acute lymphoid leukemia and is associated with intermediate to poor outcome. The specific signaling pathways downstream of MA9 are still poorly understood. We have recently described a model system whereby we expressed the MA9 fusion gene in human CD34(+) Umbilical Cord Blood (UCB) cells and showed that these cells transformed to acute myeloid or lymphoid leukemia when injected into immunodeficient mice. The Mixed Lineage Leukemia (MLL) oncogenes are unique in this model system in that they promote full transformation of primary human blood cells, while all other leukemia-associated oncogenes tested thus far have induced only partial phenotypes. Here we provide an update on the use of this system for modeling human leukemia and its potential application for therapeutic testing of novel compounds to treat the disease. We focus specifically on the Rho family of small guanosine triphosphatases (GTPases) as potential therapeutic targets, which we have implicated in the pathogenesis of AML associated with MA9 expression.
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PMID:Transforming human blood stem and progenitor cells: a new way forward in leukemia modeling. 1894 48

To study the oncogenic role of the NRAS oncogene (NRAS(G12V)) in the context of acute myeloid leukemia (AML), we used a Vav promoter-tetracycline transactivator (Vav-tTA)-driven repressible TRE-NRAS(G12V) transgene system in Mll-AF9 knock-in mice developing AML. Conditional repression of NRAS(G12V) expression greatly reduced peripheral white blood cell (WBC) counts in leukemia recipient mice and induced apoptosis in the transplanted AML cells correlated with reduced Ras/Erk signaling. After marked decrease of AML blast cells, myeloproliferative disease (MPD)-like AML relapsed characterized by cells that did not express NRAS(G12V). In comparison with primary AML, the MPD-like AML showed significantly reduced aggressiveness, reduced myelosuppression, and a more differentiated phenotype. We conclude that, in AML induced by an Mll-AF9 transgene, NRAS(G12V) expression contributes to acute leukemia maintenance by suppressing apoptosis and reducing differentiation of leukemia cells. Moreover, NRAS(G12V) oncogene has a cell nonautonomous role in suppressing erythropoiesis that results in the MPD-like AML show significantly reduced ability to induce anemia. Our results imply that targeting NRAS or RAS oncogene-activated pathways is a good therapeutic strategy for AML and attenuating aggressiveness of relapsed AML.
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PMID:RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia. 1895 98

Mutations of leukaemia associated AF9/MLLT3 are implicated in neurodevelopmental diseases such as epilepsia and ataxia. This study shows for the first time, that murine Af9 is transcribed in various CNS structures including the subventricular zone (SVZ) of the cerebral cortex, hippocampus, cerebellar cortex, septum and various thalamic structures, the choroid plexus, and the midbrain/hindbrain boundary. Expression of Af9 in the SVZ overlaps with Svet1, Cux2, and partially with Tbr2, confining its activity to the neurogenic compartment of the SVZ. In contrast to Svet1 and Cux2 expression, Af9 transcription is not limited to upper layer neurons but is found in the entire cortical plate. As part of an extensive network of interacting proteins involved in epigenetic DNA modification, we could show overlapping expression of Af9 with Af4/Aff1 and Fmr2/Aff2, two genes that are also related to neurodevelopmental diseases, as well as with the highly homologous Enl.
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PMID:Expression of Leukaemia associated transcription factor Af9/Mllt3 in the cerebral cortex of the mouse. 1900 Jul 83

Leukemias with MLL rearrangements are characterized by high expression of the homeobox gene MEIS1. In these studies, we knocked down Meis1 expression by shRNA lentivirus transduction in murine Mll-AF9 leukemia cells. Meis1 knockdown resulted in decreased proliferation and survival of murine Mll-AF9 leukemia cells. We also observed reduced clonogenic capacity and increased monocytic differentiation. The establishment of leukemia in transplantation recipients was significantly delayed by Meis1 knockdown. Gene expression profiling of cells transduced with Meis1 shRNA showed reduced expression of genes associated with cell cycle entry and progression. shRNA-mediated knockdown of MEIS1 in human MLL-fusion gene leukemia cell lines resulted in reduced cell growth. These results show that MEIS1 expression is important for MLL-rearranged leukemias and suggest that MEIS1 promotes cell-cycle entry. Targeting MEIS1 may have therapeutic potential for treating leukemias expressing this transcription factor.
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PMID:A role for MEIS1 in MLL-fusion gene leukemia. 2043 Sep 67

Chromosomal translocations involving the Mixed Lineage Leukemia (MLL) gene produce chimeric proteins that cause abnormal expression of a subset of HOX genes and leukemia development. Here, we show that MLL normally regulates expression of mir-196b, a hematopoietic microRNA located within the HoxA cluster, in a pattern similar to that of the surrounding 5' Hox genes, Hoxa9 and Hoxa10, during embryonic stem (ES) cell differentiation. Within the hematopoietic lineage, mir-196b is most abundant in short-term hematopoietic stem cells and is down-regulated in more differentiated hematopoietic cells. Leukemogenic MLL fusion proteins cause overexpression of mir-196b, while treatment of MLL-AF9 transformed bone marrow cells with mir-196-specific antagomir abrogates their replating potential in methylcellulose. This demonstrates that mir-196b function is necessary for MLL fusion-mediated immortalization. Furthermore, overexpression of mir-196b was found specifically in patients with MLL associated leukemias as determined from analysis of 55 primary leukemia samples. Overexpression of mir-196b in bone marrow progenitor cells leads to increased proliferative capacity and survival, as well as a partial block in differentiation. Our results suggest a mechanism whereby increased expression of mir-196b by MLL fusion proteins significantly contributes to leukemia development.
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PMID:Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. 1918 69

Chromatin modifications play crucial roles in various biological processes. An increasing number of conserved protein domains, often found in multisubunit protein complexes, are involved in establishing and recognizing different chromatin modifications. The YEATS domain is one of these domains, and its role in chromatin modifications and transcription is just beginning to be appreciated. The YEATS domain family of proteins, conserved from yeast to human, contains over 100 members in more than 70 eukaryotic species. Yaf9, Taf14, and Sas5 are the only YEATS domain proteins in Saccharomyces cerevisiae. Human YEATS domain family members, such as GAS41, ENL, and AF9, have a strong link to cancer. GAS41 is amplified in glioblastomas and astrocytomas; ENL and AF9 are among the most frequent translocation partners of the mixed lineage leukemia (MLL) gene. This review will focus on the best characterized YEATS proteins, discuss their diverse roles, and reflect potential functions of the YEATS domain.
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PMID:YEATS domain proteins: a diverse family with many links to chromatin modification and transcription. 1923 24

Chromosomal rearrangements of the human MLL gene are associated with high-risk pediatric, adult and therapy-associated acute leukemias. These patients need to be identified, treated appropriately and minimal residual disease was monitored by quantitative PCR techniques. Genomic DNA was isolated from individual acute leukemia patients to identify and characterize chromosomal rearrangements involving the human MLL gene. A total of 760 MLL-rearranged biopsy samples obtained from 384 pediatric and 376 adult leukemia patients were characterized at the molecular level. The distribution of MLL breakpoints for clinical subtypes (acute lymphoblastic leukemia, acute myeloid leukemia, pediatric and adult) and fused translocation partner genes (TPGs) will be presented, including novel MLL fusion genes. Combined data of our study and recently published data revealed 104 different MLL rearrangements of which 64 TPGs are now characterized on the molecular level. Nine TPGs seem to be predominantly involved in genetic recombinations of MLL: AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, MLLT4/AF6, ELL, EPS15/AF1P, MLLT6/AF17 and SEPT6, respectively. Moreover, we describe for the first time the genetic network of reciprocal MLL gene fusions deriving from complex rearrangements.
Leukemia 2009 Aug
PMID:New insights to the MLL recombinome of acute leukemias. 1926 98

The study was aimed to investigate the fusion gene transcript and immunophenotypic characteristics of the mixed linage leukemia (MLL)-rearranged positive childhood acute lymphoblastic leukemia (ALL). The incidence of MLL rearrangement in 601 cases of ALL patients was detected by the multiple-nested polymerase chain reaction (PCR); the subtypes and features of the fusion gene transcript were analyzed by PCR products sequencing; the immunophenotypic characteristics at diagnosis were compared between the 22 MLL rearrangement positive of ALL patient, 30 negative control which selected randomly from the patients whose fusion gene could not be detected in the same term and 43 pro-B-ALL patients. The results showed that the incidence of MLL positive ALL was 3.66%, constituted 29.9% of the pro-B-ALL. The MLL rearrangement positive 20 B-ALL patients were all CD10 negative; the number of patients who carried CD13, CD33 and CD34 was lower than that of pro-B-ALL who had no fusion gene, whereas the expression of CD20, CD22, CD2, CD5, CD7 showed no difference. 4 kind partner genes of MLL-AF4, AF9, AF10 and ENL were detected. The fusion loci of MLL gene were mainly located at the exon 6, 7, 8 and many kind of fusion loci of MLL may exist in one patient; whereas its partner gene fusion loci were relatively single. A transcript contains a random insert sequence existed in a transcript of one MLL-AF10+ patient. It is concluded that though incidence of MLL rearrangement is low, but it has a variety of fusion transcripts, the ALL patients has unique biological characteristics at immunophenotype and fusion transcript.
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PMID:[Characteristics of fusion gene and immunophenotype in MLL gene rearrangement positive childhood acute lymphoblastic leukemia]. 1984 Apr 68


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