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MLL-rearranged infant acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia characterized by a unique gene-expression 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. [ABSTRACT FROM AUTHOR]

MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is the most aggressive type of childhood leukemia. To develop more suitable treatment strategies, a firm understanding of the biology underlying this disease is of utmost importance. MLL-rearranged ALL displays a unique gene expression profile, partly explained by erroneous histone modifications. We recently showed that t(4;11)-positive infant ALL is also characterized by pronounced promoter CpG hypermethylation. In this study, we investigated whether this widespread hypermethylation also affected microRNA (miRNA) expression. We identified 11 miRNAs that were downregulated in t(4;11)-positive infant ALL as a consequence of CpG hypermethylation. Seven of these miRNAs were re-activated after exposure to the de-methylating agent Zebularine. Interestingly, five of these miRNAs are associated either with MLL or MLL fusions, and for miR-152 we found both MLL and DNA methyltransferase 1 (DNMT1) as potential targeted genes. Finally, a high degree of methylation of the miR-152 CpG island was strongly correlated with a poor clinical outcome. Our data suggests that inhibitors of methylation have a potential beyond re-expression of hypermethylated protein-coding genes in t(4;11)-positive infant ALL. In this study, we provide additional evidence that they should be tested for their efficacy in MLL-rearranged infant ALL in in vivo models. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented discussing variable clinical course of chronic lymphocytic leukaemia (CLL).

The severe combined immunodeficient (SCID) mouse model may be used to evaluate new approaches for the treatment of acute myeloid leukemia (AML). We have previously demonstrated the killing of SCID mouse leukemia initiating cells by in vitro incubation with human GM-CSF fused to Diphtheria toxin (DT-huGM-CSF). In this report, we show that in vivo treatment with DT-huGM-CSF eliminates AML growth in SCID mice. Seven cases of AML were studied. SCID mice were treated intraperitoneally with the maximally tolerated dose of 75 microg/kg/day for 7 days. Antileukemic efficacy was determined at days 40 and 80 after transplantation, by enumerating the percentages of human cells in SCID bone marrow using flow cytometry and short tandem repeat polymerase chain reaction (STR-PCR) analysis. Four out of seven AML cases were sensitive to in vivo treatment with DT-huGM-CSF at both evaluation time points. In three of these cases, elimination of human cells was demonstrated by flow cytometry and STR-PCR. One AML case showed moderate sensitivity for DT-huGM-CSF, and growth of the two remaining AML cases was not influenced by DT-huGM-CSF. Sensitivity was correlated with GM-CSFR expression. Our data show that DT-huGM-CSF can be used in vivo to reduce growth of AML and warrant further development of DT-huGM-CSF for the treatment of human AML. [ABSTRACT FROM AUTHOR]

We have previously demonstrated that diphtheria toxin (DT) fused to human GM-CSF effectively eliminates human long-term leukemia initiating cells in SCID mice. However, because huGM-CSF does not react with the murine GM-CSF receptor possible side-effects to nonleukemic tissues could not be analyzed in the AML/SCID model. To overcome this problem, we used murine GM-CSF fused to DT and studied the therapeutic index in the rat leukemia model BNML/LT12. In DT-mGM-CSF dose escalation experiments, severe dose-dependent toxicity to organs such as liver, kidney and lung was observed. Therefore, the antileukemic effects were evaluated with the lower doses. Daily intraperitoneal bolus injections of 75 microg/kg/day for 7 days induced a 3 log leukemic cell kill. The dose of 75 microg/kg/day had no effect on the hemopoietic progenitor cell subsets. These in vivo studies show that the DT-GM-CSF fusion protein can be used for specifically targeting leukemic cells and thus has potential as a therapeutic agent in the treatment of AML. [ABSTRACT FROM AUTHOR]

The article discusses a study that examines whether gossypol, through the induction of protein NOXA, would sensitize chronic lymphocytic leukemia (CLL) cells to B-cell lymphoma 2 (BCL2) inhibitor ABT-737. It found that gossypol resensitized the CCL cells to ABT-737 in a concentration-dependent manner. It suggests that normal lymphocytes and platelets are resistant to the combination of ABT-737 and gossypol, which offers a therapeutic window to selectively kill CLL cells.