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The t(15;17) is the diagnostic hallmark of acute promyelocytic leukemia (APL). As a result, the RARA and the promyelocytic leukemia (PML) genes are fused. The use of reverse-transcription polymerase chain reaction (RT-PCR) for the detection of the PML-RARA and RARA-PML fusion genes is the only technique that defines the PML breakpoint type and that allows the definition of a correct strategy for subsequent minimal residual disease (MRD) monitoring. Standardized conditions for RT-PCR analysis of fusion transcripts from chromosome aberrations in acute leukemia, including APL, have recently been reported in the context of the Biomed-1 Concerted Action, and are described in detail in this chapter.
Methods Mol Med 2006
PMID:Diagnosis and monitoring of PML-RARA-positive acute promyelocytic leukemia by qualitative RT-PCR. 1650 81

Genetic lesions found in acute leukemia drive the pathology of the disease in addition to forming reliable classifications of prognosis. However, there is still a reasonable heterogeneity of response among cases with the same genetic lesion. Moreover, many leukemia cases have no detectable genetic marker and these cases have marked heterogeneity of response. How can we learn more about the genes and pathways involved with leukemogenesis and response in the midst of such complexity? Gene expression microarrays are experimental platforms that allow for the simultaneous evaluation of the thousands of mRNA transcripts (the 'transcriptome'). This technology has revolutionized the study of leukemia, giving insight into genes and pathways involved in disease response and the biology involved in specific translocations.
Expert Rev Mol Diagn 2006 Sep
PMID:Use of gene expression microarrays for the study of acute leukemia. 1700 7

AF4 gene, frequently translocated with mixed-lineage leukemia (MLL) in childhood acute leukemia, encodes a putative transcriptional activator of the AF4/LAF4/FMR2 (ALF) protein family previously implicated in lymphopoiesis and Purkinje cell function in the cerebellum. Here, we provide the first evidence for a direct role of AF4 in the regulation of transcriptional elongation by RNA polymerase II (Pol II). We demonstrate that mouse Af4 functions as a positive regulator of Pol II transcription elongation factor b (P-TEFb) kinase and, in complex with MLL fusion partners Af9, Enl and Af10, as a mediator of histone H3-K79 methylation by recruiting Dot1 to elongating Pol II. These pathways are interconnected and tightly regulated by the P-TEFb-dependent phosphorylation of Af4, Af9 and Enl which controls their transactivation activity and/or protein stability. Consistently, increased levels of phosphorylated Pol II and methylated H3-K79 are observed in the ataxic mouse mutant robotic, an over-expression model of Af4. Finally, we confirm the functional relevance of Af4, Enl and Af9 to the regulation of gene transcription as their over-expression strongly stimulates P-TEFb-dependent transcription of a luciferase reporter gene. Our findings uncover a central role for these proteins in the regulation of transcriptional elongation and coordinated histone methylation, providing valuable insight into their contribution to leukemogenesis and neurodegeneration. Since these activities likely extend to the entire ALF protein family, this study also significantly inputs our understanding of the molecular basis of FRAXE mental retardation syndrome in which FMR2 expression is silenced.
Hum Mol Genet 2007 Jan 01
PMID:The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. 1713 74

Human enhancer of zeste 2 (EZH2) protein belongs to the multiprotein polycomb repressive complex 2, which also includes suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED). The polycomb repressive complex 2 complex possesses histone methyltransferase activity mediated by the Su(var)3-9, enhancer of zeste, and trithorax domain of EZH2, which methylates histone H3 on lysine (K)-27 (H3K27). In the present studies, we determined that treatment with the hydroxamate histone deacetylase inhibitor LBH589 or LAQ824 depleted the protein levels of EZH2, SUZ12, and EED in the cultured (K562, U937, and HL-60) and primary human acute leukemia cells. This was associated with decreased levels of trimethylated and dimethylated H3K27, with concomitant depletion of the homeobox domain containing HOXA9 and of MEIS1 transcription factors. Knockdown of EZH2 by EZH2 small interfering RNA also depleted SUZ12 and EED, inhibited histone methyltransferase activity, and reduced trimethylated and dimethylated H3K27 levels, with a concomitant loss of clonogenic survival of the cultured acute myelogenous leukemia (AML) cells. EZH2 small interfering RNA sensitized the AML cells to LBH589-mediated depletion of EZH2, SUZ12, and EED; loss of clonogenic survival; and LBH589-induced differentiation of the AML cells. These findings support the rationale to test anti-EZH2 treatment combined with hydroxamate histone deacetylase inhibitors as an antileukemia epigenetic therapy, especially against AML with coexpression of EZH2, HOXA9, and MEIS1 genes.
Mol Cancer Ther 2006 Dec
PMID:Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells. 1717 12

Acute leukemia, defined as a genetic disease, is the most common cancer in children representing about one half of all cancers among persons younger than 15 years. Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) each represents a heterogeneous complex of disorders, with genetic abnormalities presenting in more than 80% of ALLs and more than 90% of AMLs. The diagnostic gold standard and classification of leukaemia involves various methods including morphology, cytochemistry, cytogenetics and molecular genetics, immunophenotyping, and molecular biology. These diagnostic methods are a prerequisite for individual treatment strategies and for the evaluation of treatment response especially considering that many distinct types of acute leukemia are known to carry predictable prognoses and warrant specific therapy. The quantification of gene expression is essential in determination of tailored therapeutic decisions. Microarray technology offers the possibility of quantifying thousands of genes in a single analysis, thus potentially becoming an essential tool for molecular classification to be used in routine leukaemia diagnostics. MLL+ leukaemia is a perfect example as to the exact correspondence between gene expression and protein expression evaluated by flow cytometry. Applying computational analysis to flow cytometry results, it is possible to distinguish the MLL+ acute leukemia from MLL- acute leukemia using as the top ranked antigen some top ranked genes described in the Microarray evaluation. Key markers discriminating different leukemia phenotypes can be identified by univariate hypothesis testing from a data set of immunophenotypic markers described by two variables, one reflecting the intensity of expression (MESF) and the other the pattern of distribution (CV). A current multi center study called Microarray Innovations in Leukemia (MILE Study) uses higher density gene chips providing nearly complete coverage of the human genome. The study which has analyzed thus far 1837 retrospective cases shows that each important leukemia subtype has a specific genetic fingerprint, meaning that different combinations of genes whose expression is linked to each subtype can be identified allowing for patient tailored therapy. Moreover, the study has achieved 97% diagnostic accuracy on samples from tested patients. Statistical analysis has shown a high concordance level between standard diagnostic procedures and those of the microarray technology--globally around 95.6%. Additionally it is possible to correctly classify some subgroups incorrectly identified using gold standard methods. Thus, from a technical viewpoint, gene expression profiling in tandem with flow cytometry should be a viable alternative to standard diagnostic approaches. Whether gene expression profiling will become a practical diagnostic alternative remains to be seen.
Blood Cells Mol Dis
PMID:Diagnosis and genetic subtypes of leukemia combining gene expression and flow cytometry. 1758 88

Members of the inhibitor of apoptosis protein (IAP) family play a role in mediating apoptosis. Studies suggest that these proteins may be a viable target in leukemia because they have been found to be variably expressed in acute leukemias and are associated with chemosensitivity, chemoresistance, disease progression, remission, and patient survival. Another promising therapeutic target, FLT3, is mutated in about one third of acute myelogenous leukemia (AML) patients; promising results have recently been achieved in clinical trials investigating the effects of the protein tyrosine kinase inhibitor PKC412 on AML patients harboring mutations in the FLT3 protein. Of growing concern, however, is the development of drug resistance resulting from the emergence of point mutations in targeted tyrosine kinases used for treatment of acute leukemia patients. One approach to overriding resistance is to combine structurally unrelated inhibitors and/or inhibitors of different signaling pathways. The proapoptotic IAP inhibitor, LBW242, was shown in proliferation studies done in vitro to enhance the killing of PKC412-sensitive and PKC412-resistant cell lines expressing mutant FLT3 when combined with either PKC412 or standard cytotoxic agents (doxorubicin and Ara-c). In addition, in an in vivo imaging assay using bioluminescence as a measure of tumor burden, a total of 12 male NCr-nude mice were treated for 10 days with p.o. administration of vehicle, LBW242 (50 mg/kg/day), PKC412 (40 mg/kg/day), or a combination of LBW242 and PKC412; the lowest tumor burden was observed in the drug combination group. Finally, the combination of LBW242 and PKC412 was sufficient to override stromal-mediated viability signaling conferring resistance to PKC412.
Mol Cancer Ther 2007 Jul
PMID:Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells. 1762 Apr 26

The RUNX1 gene encodes the alpha subunit of the core binding factor (CBF) and is a common target of genetic mutations in acute leukemia. We propose that RUNX1 is a gatekeeper gene, the disruption of which leads to the exodus of a subset of hematopoietic progenitors with increased self-renewal potential from the normal environmental controls of homeostasis. This pool of "escaped" cells is the target of secondary mutations, accumulating over time to induce the aggressive manifestation of acute leukemia. Evidence from patient and animal studies supports the concept that RUNX1 mutations are the initiating event in different leukemia subtypes, but also suggests that diverse mechanisms are used to subvert RUNX1 function. One common result is the inhibition of differentiation-but its effect impinges on different lineages and stages of differentiation, depending on the mutation or fusion partner. A number of different approaches have led to the identification of secondary events that lead to the overt acute phase; however, the majority is unknown. Finally, the concept of the "leukemia stem cell" and its therapeutic importance is discussed in light of the RUNX1 gatekeeper function.
Blood Cells Mol Dis
PMID:Gatekeeper function of the RUNX1 transcription factor in acute leukemia. 1792 Mar 12

We have correlated the clinical outcome with the level of HLA matching in 423 patients who received a transplant from a volunteer unrelated donor in the United Kingdom. HLA matching was performed at the allelic level (i.e. high-resolution) using reference strand mediated conformation analysis (RSCA) at HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1. The three-year probability of overall survival (OS) was 45% (median survival of 593 days; six-year overall survival probability was 40%). The mean follow-up was 1013 days (range 89-2697). Those matched for their HLA loci had a significantly better overall survival than the mismatched pairs (47% versus 40%, p=0.040). This result could be refined based on the number of alleles that were mismatched. In patients with a single HLA mismatch, the overall survival was 43%, compared to 30% in those with multiple mismatches; however, there was no statistically significant difference between matched pairs or those with one mismatch. Although there was no significant difference in the overall survival dependent on DPB1 matching in the group overall, in acute lymphocytic leukemia, DPB1-matched pairs had a significantly worse overall survival (log rank; p=0.025). Thus, a match for DPB1 is associated with a significantly increased risk of disease relapse, irrespective of the matching status for the other HLA molecules. In a multivariate analysis, a high pre-transplant levels of Tregs resulted in worse overall survival (relative risk (RR), 2.74; p=0.01), a trend to reduce disease-free survival (RR, 2.05; p=0.060) and to increase disease relapse (RR, 3.36; p=0.006). Residual patient CD4(+)CD25(hi) regulatory T cells may suppress graft-versus-tumour responses, decreasing the overall survival by increasing the rates of relapse. In acute leukemia, the presence of NOD2/CARD15 SNPs in the genotype of unrelated donor hematopoietic stem cell transplant pairs results in significant increases in disease relapse and consequently in death. These data show an important role for NOD2/CARD15 genotyping in transplantation and suggest a possible effect of the NOD2 protein in alloreactivity and tumour surveillance. Genotyping recipients and donors prior to transplant may present valuable information for planning and management of pre-transplant conditioning regimens, and for prognosis of the outcome.
Blood Cells Mol Dis
PMID:Immunogenetic factors in donors and patients that affect the outcome of hematopoietic stem cell transplantation. 1796 96

As only 60% of leukaemia patients find a matched donor, the Perugia Bone Marrow Transplant Centre developed transplantation from HLA haplotype-mismatched family donors to provide a cure for more patients [F. Aversa, A. Tabilio, A. Terenzi, et al., Successful engraftment of T-cell-depleted haploidentical "three-loci" incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum, Blood 84 (1994) 3948-3955] [F. Aversa, A. Tabilio, A. Velardi, et al., Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype, N. Engl. J. Med. 339 (1998) 1186-1193] [F. Aversa, A. Terenzi, A. Tabilio, et al., Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse, J. Clin. Oncol. 23 (2005) 3447-3454]. HLA-mismatches trigger donor vs. recipient NK cell alloreactivity which improves engraftment, protects from GvHD and reduces relapse in AML patients [L. Ruggeri, M. Capanni, E. Urbani, et al., Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants, Science 295 (2002) 2097-2100], [L. Ruggeri, A. Mancusi, M. Capanni, E. Urbani, A. Carotti, T. Aloisi, M. Stern, D. Pende, K. Perruccio, E. Burchielli, F. Topini, E. Bianchi, F. Aversa, M.F. Martelli, A. Velardi, Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value, Blood, in press]. We are using murine transplant models to determine whether NK cell alloreactivity can be exploited to reduce transplant-related mortality (TRM) which remains a major issue. Data from these on-going studies show pre-transplant infusion of alloreactive NK cells: (1) ablates AML cells, (2) kills recipient T cells, permitting a reduced toxicity conditioning regimen, and (3) ablates the recipient dendritic cells (DCs) which trigger GvHD, thus protecting from GvHD while permitting a higher T cell content in the graft. We are designing a clinical haploidentical transplant trial using alloreactive NK cells in the conditioning regimen, with the aim of reducing TRM and improving outcomes and overall survival.
Blood Cells Mol Dis
PMID:NK cell alloreactivity and allogeneic hematopoietic stem cell transplantation. 1796 28

The histone H3 lysine 79 methyltransferase DOT1L/KMT4 can promote an oncogenic pattern of gene expression through binding with several MLL fusion partners found in acute leukemia. However, the normal function of DOT1L in mammalian gene regulation is poorly understood. Here we report that DOT1L recruitment is ubiquitously coupled with active transcription in diverse mammalian cell types. DOT1L preferentially occupies the proximal transcribed region of active genes, correlating with enrichment of H3K79 di- and trimethylation. Furthermore, Dot1l mutant fibroblasts lacked H3K79 di- and trimethylation at all sites examined, indicating that DOT1L is the sole enzyme responsible for these marks. Importantly, we identified chromatin immunoprecipitation (ChIP) assay conditions necessary for reliable H3K79 methylation detection. ChIP-chip tiling arrays revealed that levels of all degrees of genic H3K79 methylation correlate with mRNA abundance and dynamically respond to changes in gene activity. Conversion of H3K79 monomethylation into di- and trimethylation correlated with the transition from low- to high-level gene transcription. We also observed enrichment of H3K79 monomethylation at intergenic regions occupied by DNA-binding transcriptional activators. Our findings highlight several similarities between the patterning of H3K4 methylation and that of H3K79 methylation in mammalian chromatin, suggesting a widespread mechanism for parallel or sequential recruitment of DOT1L and MLL to genes in their normal "on" state.
Mol Cell Biol 2008 Apr
PMID:DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. 1828 65


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