SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia.

Constitutional dominant loss-of-function mutations in the SPRED1 gene cause a rare phenotype referred as neurofibromatosis type 1 (NF1)-like syndrome or Legius syndrome, consisted of multiple café-au-lait macules, axillary freckling, learning disabilities and macrocephaly. SPRED1 is a negative regulator of the RAS MAPK pathway and can interact with neurofibromin, the NF1 gene product. Individuals with NF1 have a higher risk of haematological malignancies. SPRED1 is highly expressed in haematopoietic cells and negatively regulates haematopoiesis. SPRED1 seemed to be a good candidate for leukaemia predisposition or transformation. We performed SPRED1 mutation screening and expression status in 230 paediatric lymphoblastic and acute myeloblastic leukaemias (AMLs). We found a loss-of-function frameshift SPRED1 mutation in a patient with Legius syndrome. In this patient, the leukaemia blasts karyotype showed a SPRED1 loss of heterozygosity, confirming SPRED1 as a tumour suppressor. Our observation confirmed that acute leukaemias are rare complications of the Legius syndrome. Moreover, SPRED1 was significantly decreased at RNA and protein levels in the majority of AMLs at diagnosis compared with normal or paired complete remission bone marrows. SPRED1 decreased expression correlated with genetic features of AML. Our study reveals a new mechanism which contributes to deregulate RAS MAPK pathway in the vast majority of paediatric AMLs.

RET fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation.

Myeloproliferative neoplasms are frequently associated with aberrant constitutive tyrosine kinase (TK) activity resulting from chimaeric fusion genes or point mutations such as BCR-ABL1 or JAK2 V617F. We report here the cloning and functional characterization of two novel fusion genes BCR-RET and FGFR1OP-RET in chronic myelomonocytic leukemia (CMML) cases generated by two balanced translocations t(10;22)(q11;q11) and t(6;10)(q27;q11), respectively. The two RET fusion genes leading to the aberrant activation of RET, are able to transform hematopoietic cells and skew the hematopoietic differentiation program towards the monocytic/macrophage lineage. The RET fusion genes seem to constitutively mimic the same signaling pathway as RAS mutations frequently involved in CMML. One patient was treated with Sorafenib, a specific inhibitor of the RET TK function, and demonstrated cytological and clinical remissions.

Expression of CD34 and CD7 on human T-cell acute lymphoblastic leukemia discriminates functionally heterogeneous cell populations.

Leukemia-initiating/repopulating cells (LICs), also named leukemic stem cells, are responsible for propagating human acute leukemia. Although they have been characterized in various leukemias, their role in T-cell acute lymphoblastic leukemia (T-ALL) is unclear. To identify and characterize LICs in T-ALL (T-LIC), we fractionated peripheral blood cell populations from patient samples by flow cytometry into three cell fractions by using two markers: CD34 (a marker of immature cells and LICs) and CD7 (a marker of early T-cell differentiation). We tested these populations in both in vitro culture assays and in vivo for growth and leukemia development in immune-deficient mice. We found LIC activity in CD7(+) cells only as CD34(+)CD7(-) cells contained normal human progenitors and hematopoietic stem cells that differentiated into T, B lymphoid and myeloid cells. In contrast, CD34(+)CD7(+) cells were enriched in LICs, when compared with CD34(-)CD7(+) cells. These CD34(+)CD7(+) cells also proliferated more upon NOTCH activation than CD34(-)CD7(+) cells and were sensitive to dexamethasone and NOTCH inhibitors. These data show that CD34 and CD7 expression in human T-ALL samples help in discriminating heterogeneous cell populations endowed with different LIC activity, proliferation capacity and responses to drugs.

[Measurement of gastric mucosal pH by tonometry in major abdominal surgery]. / Mesure du pH intramuqueux gastrique par tonométrie au cours de la chirurgie abdominale majeure.

OBJECTIVE: To investigate whether changes in gastric intramucosal pH (pHim) occur during major abdominal surgery, and if so, to determine the relationship between classic global indices of tissue perfusion such as mean arterial blood pressure (MAP), heart rate (HR), central venous pressure (CVP), urine flow (UF) and arterial pH (pHa). STUDY DESIGN: Prospective descriptive study. PATIENTS: Seven ASA2 patients undergoing major abdominal surgery. METHODS: After induction of anaesthesia and endotracheal intubation, a tonometer nasogastric tube was positioned in the stomach. Measurements of tonometric PCO2 (PCO2ss), end-tidal PCO2 (PETCO2), PaCO2, bicarbonates [bicarb], pHa, MAP, HR, CVP and UF were collected at baseline (HO), and one, two, three, and 24 hours (H1, H2, H3, and H24) after the beginning of surgery. RESULTS: Haemodynamics did not significantly change during anaesthesia. During recovery HR increased and CVP decreased significantly. The pHim decreased significantly from 7.42 +/- 0.03 at H0 to 7.30 +/- 0.02 at H3. This was associated with a significant decrease in pHa (from 7.43 +/- 0.02 at H0 to 7.33 +/- 0.02 at H3) and in [bicarbo] from 22 +/- 1 mmol at H0 to 20 +/- 1 mmol at H3). The PaCO2 increased significantly from 33.5 +/- 1.5 mmHg at H0 to 39.5 +/- 2.8 at H3. On the other hand, pHimcorr (7.40- (pHa-pHim) and delta CO2 (PCO2ss-PETCO2) did not vary during anaesthesia. Postoperative organ failure did not occur in these patients. CONCLUSIONS: The pHim may decrease during anaesthesia without evidence of abnormal tissue perfusion. In order to avoid.