ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia.

Chronic myelomonocytic leukaemia (CMML) is a haematological disease currently classified in the category of myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) because of its dual clinical and biological presentation. The molecular biology of CMML is poorly characterized. We studied a series of 53 CMML samples including 31 cases of myeloproliferative form (MP-CMML) and 22 cases of myelodysplastic forms (MD-CMML) using array-comparative genomic hybridisation (aCGH) and sequencing of 13 candidate genes including ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, PTPN11, RUNX1, TET2 and WT1. Mutations in ASXL1 and in the genes associated with proliferation (CBL, FLT3, PTPN11, NRAS) were mainly found in MP-CMML cases. Mutations of ASXL1 correlated with an evolution toward an acutely transformed state: all CMMLs that progressed to acute phase were mutated and none of the unmutated patients had evolved to acute leukaemia. The overall survival of ASXL1 mutated patients was lower than that of unmutated patients.

Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias.

BACKGROUND: Gene mutation is an important mechanism of myeloid leukemogenesis. However, the number and combination of gene mutated in myeloid malignancies is still a matter of investigation. METHODS: We searched for mutations in the ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in 65 myelodysplastic syndromes (MDSs) and 64 acute myeloid leukemias (AMLs) without balanced translocation or complex karyotype. RESULTS: Mutations in ASXL1 and CBL were frequent in refractory anemia with excess of blasts. Mutations in TET2 occurred with similar frequency in MDSs and AMLs and associated equally with either ASXL1 or NPM1 mutations. Mutations of RUNX1 were mutually exclusive with TET2 and combined with ASXL1 but not with NPM1. Mutations in FLT3 (mutation and internal tandem duplication), IDH1, IDH2, NPM1 and WT1 occurred primarily in AMLs. CONCLUSION: Only 14% MDSs but half AMLs had at least two mutations in the genes studied. Based on the observed combinations and exclusions we classified the 12 genes into four classes and propose a highly speculative model that at least a mutation in one of each class is necessary for developing AML with simple or normal karyotype.

Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia.

The myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal haematological diseases characterized by ineffective haematopoiesis and predisposition to acute myeloid leukaemia (AML). The pathophysiology of MDSs remains unclear. A definition of the molecular biology of MDSs may lead to a better classification, new prognosis indicators and new treatments. We studied a series of 40 MDS/AML samples by high-density array-comparative genome hybridization (aCGH). The genome of MDSs displayed a few alterations that can point to candidate genes, which potentially regulate histone modifications and WNT pathways (e.g. ASXL1, ASXL2, UTX, CXXC4, CXXC5, TET2, TET3). To validate some of these candidates we studied the sequence of ASXL1. We found mutations in the ASXL1 gene in four out of 35 MDS patients (11%). To extend these results we searched for mutations of ASXL1 in a series of chronic myelomonocytic leukaemias, a disease classified as MDS/Myeloproliferative disorder, and found mutations in 17 out of 39 patients (43%). These results show that ASXL1 might play the role of a tumour suppressor in myeloid malignancies.

Beta-thalassemia intermedia due to two novel mutations in the promoter region of the beta-globin gene.

Two novel beta-thalassemia mutations affecting the promoter region of the beta-globin gene are described. The first mutation, found in a Moroccan family, is a G-->A substitution at position -190 relative to the beta-globin gene Cap site. The second, found in an Algerian patient, is a G-->C substitution at position -56 relative to the beta-globin Cap site. These two mutations occur in a region (-50 to -300) where promoter elements important for differential control of gene expression have been described and lead to beta-thalassemia intermedia in association with a beta(0)-thalassemia mutations.

A pedagogical farm as a source of Q fever in a French city.

Q fever is a worldwide zoonosis caused by Coxiella burnetii and presents as both acute or chronic cases. The disease can be transmitted from animal reservoirs to humans by inhalation of infected aerosols. A previous study had revealed a hyperendemic focus in South France. A case-control study was carried-out in this area from 1996 to 1999. Besides the role of wind, this study stressed out the exposure to a pedagogical farm as an independent risk factor (4.7% of cases - 0 controls): Exposure to sheep and new-born animals (OR: 3.07 and 4.01 respectively) were not significant after omission of people exposed to the pedagogical farm. Such farms are visited by people who would not have any other contact with farm animals. These farms require a drastic hygiene and control. Q fever, as a public health problem, still requires further studies to identify and confirm individual behavioral risk factors.

Wind in November, Q fever in December.

Q fever, a worldwide zoonosis caused by Coxiella burnetii, can be transmitted from animal reservoirs to humans by the inhalation of infected aerosols. We investigated the epidemiology of Q fever in the Bouches-du-Rhone district of southern France, particularly the role of wind and rainfall in C. burnetii transmission. During the winter of 1998 to 1999, an unexpected number of cases were diagnosed in the area. This statistically higher incidence was associated with an increased frequency of the mistral 1 month before onset of disease, i.e., shortly after the main lambing season. These data confirm that wind plays a role in C. burnetii transmission, a factor that can be monitored but not prevented. Further studies are needed to identify and confirm preventable individual behavioral risk factors for Q fever.

Intensive sequential chemotherapy with hematopoietic growth factor support for non-Hodgkin lymphoma in patients infected with the human immunodeficiency virus.

BACKGROUND: Optimal treatment of human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL) has yet to be defined, because chemotherapy could exacerbate immunodeficiency, with subsequent adverse effects for patients. METHODS: The authors investigated the feasibility of an intensive chemotherapy regimen for HIV-associated NHL. Thirty-eight patients were treated with a first course of cyclophosphamide (Cy), vincristine, and prednisone; followed by 3 courses of high-dose Cy (2000 mg/m2), doxorubicin (Doxo; 50 mg/m2), vincristine, and prednisone (modified high-dose CHOP); 1 course of high-dose methotrexate (MTX; 8000 mg/m2); and 1 course of high-dose cytarabine (8000 mg/m2). Radiotherapy was added to the treatment regimen for patients with bulky disease or residual tumor. Chemotherapy was administered in conjunction with granulocyte-colony-stimulating factor and antiretroviral therapy. RESULTS: Patients received 91.5%, 93%, 66%, and 63% of the scheduled doses of Cy, Doxo, MTX, and cytarabine, respectively. The complete response rate was 60.5%, with a total response rate of 79%. The 40-month overall survival rate was 43%, the disease-free survival rate was 65%, and the recurrence-free survival rate was 39%. Both an International Prognostic Index score of 0 or 1 and Burkitt-type histology had positive effects on survival, whereas CD4-positive lymphocyte counts, viral burden, and previous highly active antiretroviral therapy did not. CD4-positive T lymphocyte levels decreased from 0.197 +/- 0.156 x10(9)/L before treatment to 0.152 +/- 0.1 x10(9)/L at 6 months after the end of treatment. A decrease in viral load, from 380,000 +/- 785,000 copies/mL before treatment to 25,000 +/- 43,000 copies/mL at 6 months after the end of treatment, also was observed. CONCLUSIONS: The results of the current study indicate that intensive chemotherapy is effective and tolerable for patients with HIV-associated NHL.