Role of Misfolded N-CoR Mediated Transcriptional Deregulation of Flt3 in Acute Monocytic Leukemia (AML)-M5 Subtype

The nuclear receptor co-repressor (N-CoR) is a key component of the generic multi-protein complex involved in transcriptional control. Flt3, a key regulator of hematopoietic cell growth, is frequently deregulated in AML (acute myeloid leukemia). Here, we report that loss of N-CoR-mediated transcriptional control of Flt3 due to misfolding, contributes to malignant growth in AML of the M5 subtype (AML-M5). An analysis of hematopoietic genes in AML cells led to the identification of Flt3 as a transcriptional target of N-CoR. Flt3 level was inversely related to N-CoR status in various leukemia cells. N-CoR was associated with the Flt3 promoter in-vivo, and a reporter driven by the Flt3 promoter was effectively repressed by N-CoR. Blocking N-CoR loss with Genistein; an inhibitor of N-CoR misfolding, significantly down-regulated Flt3 levels regardless of the Flt3 receptor mutational status and promoted the differentiation of AML-M5 cells. While stimulation of the Flt3 receptor with the Flt3 ligand triggered N-CoR loss, Flt3 antibody mediated blockade of Flt3 ligand-receptor binding led to N-CoR stabilization. Genetic ablation of N-CoR potentiated Flt3 ligand induced proliferation of BA/F3 cells. These findings suggest that N-CoR-induced repression of Flt3 might be crucial for limiting the contribution of the Flt3 signaling pathway on the growth potential of leukemic cells and its deregulation due to N-CoR loss in AML-M5, could contribute to malignant growth by conferring a proliferative advantage to the leukemic blasts. Therapeutic restoration of N-CoR function could thus be a useful approach in restricting the contribution of the Flt3 signaling pathway in AML-M5 pathogenesis

ALL-1/MLL1, a homologue of Drosophila TRITHORAX, modifies chromatin and is directly involved in infant acute leukaemia

Rearrangements of the ALL-1/MLL1 gene underlie the majority of infant acute leukaemias, as well as of therapy-related leukaemias developing in cancer patients treated with inhibitors of topoisomerase II, such as VP16 and doxorubicin. The rearrangements fuse ALL-1 to any of \u3e50 partner genes or to itself. Here, we describe the unique features of ALL-1-associated leukaemias, and recent progress in understanding molecular mechanisms involved in the activity of the ALL-1 protein and of its Drosophila homologue TRITHORAX

The translocation t(8;16)(p11;p13) defines an AML subtype with distinct cytology and clinical features

Twenty-five patients with AML and t(8;16)(p11;p13) and 3 patients with identical cytological and clinical features and variant translocations involving breakpoint 8p11 have been previously reported (frequency 0.4% of AML). We describe a further case of t(8;16) and review the salient features of this form of AML. Blast morphology was monocytoid but with heavy azurophilic granulation and prominent erythrophagocytosis. Non specific esterase (NSE) positivity inhibited by sodium fluoride confirms monocytic differentiation but strong peroxidase activity and dual positivity for chloroacetate esterase and NSE suggest the involvement of a common monocytic-granulocytic precursor. The prognosis appears to be worse than in typical AML M5 and CNS disease may be a particular feature at diagnosis. There are only 5 reported survivors: 3 had allogeneic bone marrow transplants. Our patient remains in remission 2 years after autologous bone marrow transplant. Breakpoint 8p11 appears to be a critical region where PLAT, the gene for tissue plasminogen activator maps. PLAT may be the key to the pathogenesis of the coagulation defect documented in one third of cases which can be due to DIC or primary fibrinolysis. The translocation t(8;16) or its variants appear to define a distinct variant of AML, M5 with erythrophagocytosis, which does not easily fit into the FAB classification

Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia.

We have analysed the prognostic influence of cytogenetic findings at diagnosis in a group of 502 children with acute lymphoblastic leukaemia (ALL), treated on MRC UKALL X, in whom clonal cytogenetic abnormalities were detected at diagnosis. Despite the overall improvement in outcome in children treated on this protocol compared with previous trials, some cytogenetically-defined groups were still associated with a poor outcome and ploidy retained some prognostic significance. Patients with high hyperdiploid ALL (39% of those with clonal abnormalities) had a favourable outcome with event free survival of 71% at 5 years. Those with near haploidy (1%), hypodiploidy (9%) and low hyperdiploidy (16.5%) had a relatively poor prognosis with event-free survival at 5 years of 17%, 42% and 49% respectively. Only two of 12 children with Ph-positive leukaemia are alive in remission and abnormalities of chromosome 11q23 were also associated with a high risk of treatment failure. In contrast, the t(1;19) was associated with improved event-free survival of 87.5% at 5 years. A number of other non-random abnormalities were identified with no clear prognostic significance. We conclude that identification of certain genetic changes remains important in the management of acute lymphoblastic leukaemia, although whether molecular diagnosis of clinically relevant abnormalities can now supplant cytogenetics in the clinical trials context remains to be determined

Chromosomes and other prognostic factors in acute lymphoblastic leukaemia: a long-term follow-up.

Cytogenetic, clinical and laboratory features at diagnosis were examined in a group of 80 children with acute lymphoblastic leukaemia (ALL) who had been followed up for a minimum of 5 1/2 years. The 17 (21%) with high hyperdiploidy tended to have low leucocyte counts and common ALL, but their favourable outcome (75% event-free survival) was independent of these factors. No patient with hypodiploidy survives while the pseudodiploid and normal groups have an intermediate prognosis. Cytogenetic analysis showed examples of patients with the well-recognized translocations and a number with apparently unique ones. Among the latter were some long-term survivors. We conclude that cytogenetic analysis identifies a good risk group of patients who remain well on long-term follow-up, but that the presence of a translocation does not necessarily imply a poor outcome