L' activité de la protéine ABCB1 est un facteur pronostique indépendant pour la réponse au traitement intensif chez 206 patients atteints de leucémie aiguë myéloïde, en tenant compte des nouveaux marqueurs moléculaires

L'activité de la protéine ABCB1 est un facteur pronostique connu dans les leucémies aiguës myéloïdes, mais n'a jamais été évaluée en comparaison des marqueurs moléculaires de découverte plus récente, comme les duplications de FLT3, les mutations de NPM1, les mutations de CEBPAQ, ou l'expression de BAALC. Par ailleurs, les relations entre ces derniers marqueurs et l'activité d'ABCB1 ont été très peu étudiées. cette étude rétrospective sur 206 patients atteints de leucémie aiguë myéloïde, et traités de manière homogène, évalue les relations entre l'activité d'ABCB1 et ces marqueurs moléculaires, et évalue si cette activité reste un facteur pronostique indépendant de réponse au traitement. Dans cette étude, 20% des patients présentent une haute activité d'ABCB1. Cette activité est associée à un compte leucocytaire plus bas, à l'absence de mutation de NPM1, et à une haute expression de BAALC et de CD 34. Les facteurs pronostiques indépendants retrouvés pour la survie globale dans la popultaion générale sont l'âge, la cytogénétique, les duplications de FLT3, et l'activité d'ABCB1. En cas de cytogénétique normale, l'âge, le compte leucocytaire et l'activité d'ABCB1sont les seuls facteurs pronostiques indépendants pour la survie sans maladie ; l'âge, les duplications de FLT3, et l'activité d'ABCB1 sont seuls facteurs pronostiques indépendants pour la survie globale. L'absence de duplication de FLT3, associée à une faible d'ABCB1, définit un groupe de patients de pronostic significativement plus favorable. L'activité d'ABCB1 reste un facteur pronostique indépendant dans les leucémies aiguës myéloïdes, et devrait être évaluée chez tous les patients au diagnostic.ST QUENTIN EN YVELINES-BU (782972101) / SudocSudocFranceF

A teacher-implemented intervention program to promote finger use in numerical tasks

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Targeting CD13 (aminopeptidase-N) in turn downregulates ADAM17 by internalization in acute myeloid leukaemia cells

International audienceSecreted matrix metalloproteinases (MMP)-2 and MMP-9 and membrane-anchored aminopeptidase-N/CD13 are abnormally expressed in human acute myeloid leukaemia (AML). We previously showed that CD13 ligation by anti-CD13 monoclonal antibodies can induce apoptosis in AML cells. Here, we assessed ADAM17 expression in primary blood blasts CD13+CD33+ from patients with AML. Primary AML cells expressed ADAM17 transcript and its surface expression was higher in subtype M4 (myelomonocytic) and M5 (monocytic) AML specimens than in M0 and M1/M2 (early and granulocytic) specimens. In AML cell lines defining distinct AML subfamilies (HL-60/M2, NB4/M3, THP-1/M5, U937/M5) and primary AML cells cultured ex vivo, anti-CD13 antibodies downregulated surface CD13 and ADAM17 without affecting MMP-2/-9 release. Knockdown of CD13 by siRNA prevented anti-CD13-mediated ADAM17 downregulation, indicating that CD13 is required for ADAM17 downregulation. Soluble ADAM17 was not detected in the medium of anti-CD13 treated cells, suggesting that ADAM17 was not shed. After ligation by anti-CD13, CD13 and ADAM17 were internalized. Subsequently, we found that ADAM17 interacts with CD13. We postulate that the interaction of ADAM17 with CD13 and its downregulation following CD13 engagement has important implications in AML for the known roles of ADAM17 in tumour-associated cell growth, migration and invasion

The antiangiogenic phloroglucinol hyperforin inhibits the secretion of proMMP-2, proMMP-9 and VEGF-A during apoptosis of primary acute myeloid leukemia cells

Aim: Angiogenesis is observed in acute myeloid leukemia (AML). AML cells abnormally proliferate and are resistant to death. Positive regulators of angiogenesis, VEGF-A and matrix metalloproteinases (MMPs) 2 and 9 are markers of disease status in AML. The natural phloroglucinol hyperforin (HF) displays antitumoral properties of potential pharmacological interest. Herein, we investigated the effects of HF on MMP-2/9 and VEGF-A expression and survival of primary AML cells.Methods: Blood and bone marrow samples were collected in 45 patients with distinct subtypes defined by French American British classification, i.e., M0, M1, M2, M3, M4, and M5. Levels of MMPs and VEGF-A in leukemic blood cells and culture supernatants were determined by RT-PCR, ELISA, and gelatin zymography (MMPs). The balance between cell death and survival was assessed by flow cytometry with analysis of phosphatidylserine externalization and caspase-3 activation.Results: The administration of HF promoted a caspase-associated apoptosis in primary AML blasts (from blood and bone marrow), but not normal blood cells and monocytes. In addition, HF inhibited the levels of secreted proMMP-2, proMMP-9, and VEGF-A without altering transcripts. The induction of apoptosis by HF significantly paralleled the inhibition of MMP-2/9 and VEGF-A release by HF. No differences were seen in response to the deleterious effects of HF between AML cells of distinct subtypes.Conclusion: Our results suggest that HF, through its proapoptotic and potential antiangiogenic properties (by inhibiting MMP-2/9 and VEGF-A) on primary AML cells, might be a useful experimental agent, in combination with existing drugs, for new therapeutic approaches in the treatment of this incurable disease

Trichosporon : another yeast-like organism responsible for immune reconstitution inflammatory syndrome in patients with hematological malignancy

International audienceTrichosporon has recently emerged as a life-threatening opportunistic fungal pathogen, notably in patients with hematological malignancy. Fungemia, sometimes associated with cu-taneous lesions and/or pneumonitis, is the major clinical form. Here, we report two cases of patients suffering from acute leukaemia who developed hepatic and/or splenic lesions apart from Trichosporon positive blood cultures. The appearance of hepatic and splenic lesions following the recovery from neutropenia is highly suggestive of a chronic disseminated infection , now considered as an immune reconstitution inflammatory syndrome. Treatment with corticosteroid therapy led to clinical improvement in both cases

Magnetic resonance spectroscopy of cellular lipid extracts from sensitive, resistant and reverting K562 cells and flow cytometry for investigating the P-glycoprotein function in resistance reversion

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Midostaurin plus daunorubicin or idarubicin for young and older adults with FLT3 -mutated AML : a phase 3b trial

The pivotal RATIFY study demonstrated midostaurin (50 mg twice daily) with standard chemotherapy significantly reduced mortality in adult patients (60 years) patients with FLT3 mut ND-AML. Compared with RATIFY, this study extended midostaurin treatment from 14 days to 21 days, substituted anthracyclines (idarubicin or daunorubicin), and introduced variation in standard combination chemotherapy dosing ("7+3" or "5+2" in more fragile patients). Total 301 patients (47.2% >60 years and 82.7% with FLT3-ITD mut ) of median age 59 years entered induction phase. Overall, 295 patients (98.0%) had at least 1 adverse event (AE), including 254 patients (84.4%) with grade ≥3 AE. The grade ≥3 serious AEs occurred in 134 patients. No difference was seen in AE frequency between age groups, but grade ≥3AE frequency was higher in older patients. Overall, complete remission (CR) rate including incomplete hematologic recovery (CR + CRi) (80.7% [95% confidence interval, 75.74-84.98]) was comparable between age groups (≤60 years [83.5%]; >60 to ≤70 years [82.5%]; in patients >70 years [64.1%]) and the type of anthracycline used in induction. CR + CRi rate was lower in males (76.4%) than females (84.4%). Overall, the safety and efficacy of midostaurin remains consistent with previous findings, regardless of age, sex, or induction regimen. The trial is registered at as #

Zosuquidar restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AML)

Abstract Background Chemotherapeutic drug efflux via the P-glycoprotein (P-gp) transporter encoded by the MDR1/ABCB1 gene is a significant cause of drug resistance in numerous malignancies, including acute leukemias, especially in older patients with acute myeloid leukemia (AML). Therefore, the P-gp modulators that block P-gp-mediated drug efflux have been developed, and used in combination with standard chemotherapy. In this paper, the capacity of zosuquidar, a specific P-gp modulator, to reverse chemoresistance was examined in both leukemia cell lines and primary AML blasts. Methods The transporter protein expressions were analyzed by flow cytometry using their specific antibodies. The protein functionalities were assessed by the uptake of their fluorescence substrates in presence or absence their specific modulators. The drug cytotoxicity was evaluated by MTT test. Results Zosuquidar completely or partially restored drug sensitivity in all P-gp-expressing leukemia cell lines tested and enhanced the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumab ozogamicin (Mylotarg) in primary AML blasts with active P-gp. In addition, P-gp inhibition by zosuquidar was found to be more potent than cyclosporine A in cells with highly active P-gp. Conclusion These in vitro studies suggest that zosuquidar may be an effective adjunct to cytotoxic chemotherapy for AML patients whose blasts express P-gp, especially for older patients.</p