Search

Oncogenic NRAS and KRAS mutations are prevalent in human juvenile and chronic myelomonocytic leukemia (JMML/CMML). However, additional genetic mutations cooperating with oncogenic RAS in JMML/ CMML progression and/or their transformation to acute myeloid leukemia (AML) remain largely unknown. Here we tested the potential genetic interaction of DNMT3A mutations and oncogenic RAS mutations in leukemogenesis. We found that Dnmt3a(-/-) induces multiple hematopoietic phenotypes after a prolonged latency, including T-cell expansion in the peripheral blood, stress erythropoiesis in the spleen and myeloid malignancies in the liver. Dnmt3a(-/-) significantly promoted JMML/CMML progression and shortened the survival of Kras(G12D/+) mice in a cell-autonomous manner. Similarly, downregulating Dnmt3a also promoted myeloid malignancies in Nras(G12D/+) mice. Further studies show that Dnmt3a deficiency rescues Kras(G12D/+)-mediated depletion of hematopoietic stem cells and increases self-renewal of Kras(G12D/+) myeloid progenitors (MPs). Moreover, ~33% of animals developed an AML-like disease, which is driven by Kras(G12D/+); Dnmt3a(-/-) MPs. Consistent with our result, COSMIC database mining demonstrates that the combination of oncogenic RAS and DNMT3A mutations exclusively occurred in patients with JMML, CMML or AML. Our results suggest that DNMT3A mutations and oncogenic RAS cooperate to regulate hematopoietic stem and progenitor cells and promote myeloid malignancies. [ABSTRACT FROM AUTHOR]

Oncogenic NRAS and KRAS mutations are prevalent in human juvenile and chronic myelomonocytic leukemia (JMML/CMML). However, additional genetic mutations cooperating with oncogenic RAS in JMML/ CMML progression and/or their transformation to acute myeloid leukemia (AML) remain largely unknown. Here we tested the potential genetic interaction of DNMT3A mutations and oncogenic RAS mutations in leukemogenesis. We found that Dnmt3a−/− induces multiple hematopoietic phenotypes after a prolonged latency, including T-cell expansion in the peripheral blood, stress erythropoiesis in the spleen and myeloid malignancies in the liver. Dnmt3a−/− significantly promoted JMML/CMML progression and shortened the survival of KrasG12D/+ mice in a cell-autonomous manner. Similarly, downregulating Dnmt3a also promoted myeloid malignancies in NrasG12D/+ mice. Further studies show that Dnmt3a deficiency rescues KrasG12D/+-mediated depletion of hematopoietic stem cells and increases self-renewal of KrasG12D/+ myeloid progenitors (MPs). Moreover, ~33% of animals developed an AML-like disease, which is driven by KrasG12D/+; Dnmt3a−/− MPs. Consistent with our result, COSMIC database mining demonstrates that the combination of oncogenic RAS and DNMT3A mutations exclusively occurred in patients with JMML, CMML or AML. Our results suggest that DNMT3A mutations and oncogenic RAS cooperate to regulate hematopoietic stem and progenitor cells and promote myeloid malignancies. [ABSTRACT FROM AUTHOR]

The bridging integrator 1 (BIN1) tumor suppressor encodes multiple alternatively spliced isoforms implicated in DNA repair, cell-cycle control, apoptosis and membrane dynamics. BIN1 attenuation has been reported in several solid tumors; however, the role of BIN1 in lymphomagenesis remains unexplored. We recently demonstrated that BIN1 transcript levels are significantly downregulated in CD4+CD7− Sezary cells from patients with Sezary syndrome (SS), a subtype of cutaneous T-cell lymphoma (CTCL). We have now demonstrated that restored BIN1 expression in CTCL cells leads to a significant reduction in cell proliferation, an increase in spontaneous and Fas/Fas ligand (Fas/FasL)-induced apoptosis in vitro and inhibition of tumorigenic activity of CTCL cells in vivo. Interestingly, restoration of BIN1 expression in CTCL cells downregulates the expression of c-FLIP, an important inhibitor of Fas/FasL-mediated apoptosis, and activates the caspase cascade; these phenotypes can be rescued by knockdown of BIN1. Importantly, significantly reduced BIN1 expression and increased c-FLIP expression are observed in primary CTCL patient samples, and high BIN1 and low c-FLIP mRNA levels correlate with better survival rate in SS patients. These results indicate that BIN1 regulates Fas/FasL-mediated apoptosis through c-FLIP and that BIN1 deficiency may have an important role in CTCL pathogenesis by causing apoptosis resistance. Thus BIN1 and c-FLIP represent potential therapeutic targets in CTCL. [ABSTRACT FROM AUTHOR]

The article presents a study exploring whether aldehyde dehydrogenase (ALDH1) multiple myeloma (MM) cells can initiate MM tumor formation as well as evaluates the functional role of ALDH1 in MM cell growth, clonogenic ability and cell signaling. The study reveals that ALDH1 myeloma cells took a significant increase in colony formation. The authors conclude that ALDH1 cells have the properties of MMSCs or MM-initiating cells including tumor initiation, drug resistance and cell proliferation.

The article presents a study which revealed that VPREB1 gene focal deletions are common in B-cell acute lymphoblastic leukemia (B-ALL) and occur independent of variable (joining) diversity (V(D)J) light chain recombination. It notes the correlation of focal deletions of VPREB1 with decreased expression levels and high-risk patients with focal deletions tend to have overall survival (OS). The central role of VPREB1 in B-cell development as part of the pre-B-cell receptor (pre-BCR) is tackled.

Cancer-causing mutations disrupt coordinated, precise programs of gene expression that govern cell growth and differentiation. Microarray-based gene-expression profiling (GEP) is a powerful tool to globally analyze these changes to study cancer biology and clinical behavior. Despite overwhelming genomic chaos in multiple myeloma (MM), expression patterns within tumor samples are remarkably stable and reproducible. Unique expression patterns associated with recurrent chromosomal translocations and ploidy changes defined molecular classes with differing clinical features and outcomes. Combined molecular techniques also dissected two distinct, reproducible forms of hyperdiploid disease and have molecularly defined MM with high risk for poor clinical outcome. GEP is now used to risk-stratify patients with newly diagnosed MM. Groups with high-risk features are evident in all GEP-defined MM classes, and GEP studies of serial samples showed that risk increases over time, with relapsed disease showing dramatic GEP shifts toward a signature of poor outcomes. This suggests a common mechanism of disease evolution and potentially reflects preferential expansion of therapy-resistant cells. Correlating GEP-defined disease class and risk with outcomes of therapeutic regimens reveals class-specific benefits for individual agents, as well as mechanistic insights into drug sensitivity and resistance. Here, we review modern genomics contributions to understanding MM pathogenesis, prognosis, and therapy. [ABSTRACT FROM AUTHOR]

There has been a steady improvement in cure rates for children with advanced-stage lymphoblastic non-Hodgkin's lymphoma. To further improve cure rates whereas minimizing long-term toxicity, we designed a protocol (NHL13) based on a regimen for childhood T-cell acute lymphoblastic leukemia, which features intensive intrathecal chemotherapy for central -nervous system-directed therapy and excludes prophylactic cranial irradiation. From 1992 to 2002, 41 patients with advanced-stage lymphoblastic lymphoma were enrolled on the protocol. Thirty patients had stage III and 11 had stage IV disease. Thirty-three cases had a precursor T-cell immunophenotype, five had precursor B-cell immunophenotype and in three immunophenotype was not determined. Out of the 41 patients, 39 (95%) achieved a complete remission. The 5-year event-free rate was 82.9+/-6.3% (s.e.), and 5-year overall survival rate was 90.2+/-4.8% (median follow-up 9.3 years (range 4.62-13.49 years)). Adverse events included two induction failures, one death from typhlitis during remission, three relapses and one secondary acute myeloid leukemia. The treatment described here produces high cure rates in children with lymphoblastic lymphoma without the use of prophylactic cranial irradiation. [ABSTRACT FROM AUTHOR]

Hyperglycemia adversely affects outcome in adult patients with acute lymphoblastic leukemia (ALL), but its impact on children with this disease is unknown. We evaluated the relationship between hyperglycemia during remission induction therapy and clinical outcomes among pediatric patients with ALL. We reviewed the records of patients enrolled on four consecutive ALL protocols (Total Therapy protocols XIIIA, XIIIB, XIV and XV) at St Jude Children's Research Hospital from 1991 to 2007 and identified those who experienced hyperglycemia (glucose >or=200 mg per 100 ml) during remission induction. Complete remission (CR) rates at the end of induction, event-free survival (EFS), overall survival (OS), cumulative incidence of relapse and occurrence of infections were compared between those who did and did not experience hyperglycemia. Of 871 patients analyzed, 141 (16%) experienced hyperglycemia during remission induction. Patients with hyperglycemia were significantly older than the other patients (P<0.0001). There was no significant difference in CR rate (P=0.92), EFS (P=0.80), OS (P=0.28), cumulative incidence of relapse (P=0.59) or in the probability or types of infection between patients who did and did not experience hyperglycemia. Pediatric patients with or without hyperglycemia during remission induction for ALL have similar clinical outcome. Occurrence of hyperglycemia does not warrant alteration of the antileukemic regimen. [ABSTRACT FROM AUTHOR]

Ahi-1 (Abelson helper integration site 1) is a novel gene frequently activated by provirus insertional mutagenesis in murine leukemias and lymphomas. Its involvement in human leukemogenesis is demonstrated by gross perturbations in its expression in human leukemia cells, particularly in cutaneous T-cell lymphoma cell lines where increases in AHI-1 transcripts of 40-fold are seen. To test directly whether deregulated expression of AHI-1 contributes to their transformed properties, knockdown of AHI-1 expression in Hut78 cells, a cell line derived from a patient with Sezary syndrome (SS), was performed using retroviral-mediated RNA interference. Retroviral-mediated suppression specifically inhibited expression of AHI-1 and its isoforms in transduced cells by 80% and also reduced autocrine production of interleukin (IL)-2, IL-4 and tumor necrosis factor-alpha (TNFα) by up to 85%. It further significantly reduced their growth factor independence in vitro and the ability to produce tumors in immunodeficient mice. Interestingly, aberrant expression of AHI-1, particularly truncated isoforms, was present in CD4+CD7− Sezary cells from some patients with SS. Elevated expression of IL-2 and TNFα was also found in these cells. These findings provide strong evidence of the oncogenic activity of AHI-1 in human leukemogenesis and demonstrate that its deregulation may contribute to the development of SS.Leukemia (2006) 20, 1593–1601. doi:10.1038/sj.leu.2404321; published online 13 July 2006 [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) codes for 13 respiratory chain subunits and is more vulnerable to damage than nuclear DNA due, in part, to a lack of histone protection and a weak repair capacity. While mtDNA alterations have been observed in human cancer, their roles in oncogenesis and chemosensitivity remain unclear. We investigated the relationship between mtDNA mutations, reactive oxygen species (ROS) generation, and clinical outcomes in chronic lymphocytic leukemia (CLL) patients. An analysis of mtDNA from 20 CLL patients revealed that primary CLL cells from patients with prior chemotherapy had a significantly higher frequency of heteroplasmic mutations than did those from untreated patients. Overall, mtDNA mutations appeared to be associated with increased ROS generation. Patients refractory to conventional therapeutic agents tended to have higher mutation rates than patients who responded to treatment. Analysis of paired blood samples from the same patient led to the identification of a hetero-plasmic mutation in the cytochrome c oxidase II gene several months after chemotherapy. The mutation was associated with increased ROS generation. Our results suggest for the first time that chemotherapy with DNA-damaging agents may cause mtDNA mutations in primary leukemia cells, which often exist in heteroplasmy, and are associated with increased ROS generation. [ABSTRACT FROM AUTHOR]

An increasing number of risk-stratifying genetic lesions in acute leukemia are being discovered and characterized. To translate this important and increasing volume of information from the research laboratory into effective clinical care, however, new, fast and comprehensive assays are needed. Toward this end, we have developed a two-stage multiplexing assay of broad applicability, which combines multiplex polymerase chain reaction with multiplex detection on spectrally addressable liquid bead microarrays. Using pediatric lymphoblastic leukemia as a model system, we demonstrate that all seven of the fusion transcripts resulting from risk-stratifying chromosomal translocations can be assayed in a single well of a 96-well multiplate with 100% specificity and sensitivity, within 6 h of specimen collection. The assay is automatic and high throughput and represents a significant improvement over previously available assays targeting the same genetic changes. We conclude that user-defined assays that multiplex both target selection and detection may have broad applicability in the management of hematological malignancies. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a study which investigates calreticulin mutations in Chinese patients diagnosed with essential thrombocythemia (ET), also known as primary myelofibrosis (PMF).