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1. CPX-351 in higher risk myelodysplastic syndrome and chronic myelomonocytic leukaemia: a multicentre, single-arm, phase 2 study

Author

Peterlin, Pierre, Le Bris, Yannick, Turlure, Pascal, Chevallier, Patrice, Ménard, Audrey, Gourin, Marie-Pierre, Dumas, Pierre-Yves, Thepot, Sylvain, Berceanu, Ana, Park, Sophie, Hospital, Marie-Anne, Cluzeau, Thomas, Bouzy, Simon, Torregrosa-Diaz, Jose-Miguel, Drevon, Louis, Sapena, Rosa, Chermat, Fatiha, Ades, Lionel, Dimicoli-Salazar, Sophie, Chevret, Sylvie, Béné, Marie-Christine, and Fenaux, Pierre

Published
2023
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3. Role of red cell mass evaluation in myeloproliferative neoplasms with splanchnic vein thrombosis and normal hemoglobin value: a study of the France Intergroupe des Syndromes myeloprolifératifs

Author

Galtier, Jean, primary, Drevon, Louis, additional, Le Bris, Yannick, additional, Giraudier, Stephane, additional, Wemeau, Mathieu, additional, Legros, Laurence, additional, Paz, Damien Luque, additional, Girodon, François, additional, Kiladjian, Jean-Jacques, additional, Mesguich, Charles, additional, Parrens, Marie, additional, Mediavilla, Clémence, additional, Roy, Lydia, additional, Guy, Alexandre, additional, Mansier, Olivier, additional, Ianotto, Jean-Christophe, additional, and James, Chloe, additional

Published
2024
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4. Reduced murine double minute 2 and 4 protein, but not messenger RNA, expression is associated with more severe disease in myelodysplastic syndromes and acute myeloblastic leukaemia

Author

Salomao, Norman, Maslah, Nabih, Giulianelli, Anouk, Drevon, Louis, Aguinaga, Lorea, Gu, Xiaolian, Cassinat, Bruno, Giraudier, Stephane, Fenaux, Pierre, Fåhraeus, Robin, Salomao, Norman, Maslah, Nabih, Giulianelli, Anouk, Drevon, Louis, Aguinaga, Lorea, Gu, Xiaolian, Cassinat, Bruno, Giraudier, Stephane, Fenaux, Pierre, and Fåhraeus, Robin

Abstract

The human homologues of murine double minute 2 (MDM2) and 4 (MDM4) negatively regulate p53 tumour suppressor activity and are reported to be frequently overexpressed in human malignancies, prompting clinical trials with drugs that prevent interactions between MDM2/MDM4 and p53. Bone marrow samples from 111 patients with acute myeloblastic leukaemia, myelodysplastic syndrome or chronic myelomonocytic leukaemia were examined for protein (fluorescence-activated cell sorting) and messenger RNA (mRNA) expression (quantitative polymerase chain reaction) of MDM2, MDM4 and tumour protein p53 (TP53). Low protein expression of MDM2 and MDM4 was observed in immature cells from patients with excess of marrow blasts (>5%) compared with CD34+/CD45low cells from healthy donors and patients without excess of marrow blasts (<5%). The mRNA levels were indistinguishable in all samples examined regardless of disease status or blast levels. Low MDM2 and MDM4 protein expression were correlated with poor survival. These data show a poor correlation between mRNA and protein expression levels, suggesting that quantitative flow cytometry analysis of protein expression levels should be used to predict and validate the efficacy of MDM2 and MDM4 inhibitors. These findings show that advanced disease is associated with reduced MDM2 and MDM4 protein expression and indicate that the utility of MDM2 and MDM4 inhibitors may have to be reconsidered in the treatment of advanced myeloid malignancies.

Published
2023
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5. Reduced murine double minute 2 and 4 protein, but not messenger RNA , expression is associated with more severe disease in myelodysplastic syndromes and acute myeloblastic leukaemia

Author

Salomao, Norman, primary, Maslah, Nabih, additional, Giulianelli, Anouk, additional, Drevon, Louis, additional, Aguinaga, Lorea, additional, Gu, Xiaolian, additional, Cassinat, Bruno, additional, Giraudier, Stephane, additional, Fenaux, Pierre, additional, and Fahraeus, Robin, additional

Published
2022
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6. In silico and Functional Studies for Classification of EPAS1/HIF2A Genetic Variants Identified in Patients with Erythrocytosis

Author

Karaghiannis, Valéna, primary, Maric, Darko, additional, Garrec, Céline, additional, Maaziz, Nada, additional, Buffet, Alexandre, additional, Antunes, Vincent, additional, le Roy, Amandine, additional, Airaud, Fabrice, additional, Aral, Bernard, additional, Schmitt, Loic, additional, Corbineau, Sébastien, additional, Mansour-Hendili, Lamisse, additional, Lesieur, Valentine, additional, Rimbert, Antoine, additional, Laporte, Fabien, additional, Delamare, Marine, additional, Bezieau, Stephane, additional, Cassinat, Bruno, additional, Galactéros, Frédéric, additional, Gimenez-Roqueplo, Anne-Paule, additional, Burnichon, Nelly, additional, Cario, Holger, additional, Wijk, Richard van, additional, Bento, Celeste, additional, Blouet, Anaise, additional, Bouteloup, Juliette, additional, Boyer perrard, Françoise, additional, Bruce, Aisha Aiko, additional, Cayssials, Emilie, additional, Casadevall, Nicole, additional, Cherel, Brieuc, additional, Couec, Marielaure, additional, Drevon, Louis, additional, Dumesnil, Cecile, additional, Lamy De La Chapelle, Thierry, additional, Gambart, Marion, additional, Garcon, Loic, additional, Granel, Brigitte, additional, Hirsch, Pierre, additional, Lahary, Agnès, additional, Mejri, Amira, additional, Meunier, Sandrine, additional, Nicolini, Franck E., additional, Raffoux, Emmanuel, additional, Ranta, Dana, additional, Schleinitz, Nicolas, additional, Valentin, Jean Baptiste, additional, Wemeau, Mathieu, additional, Girodon, Francois, additional, Hoogewijs, David, additional, Gardie, Betty, additional, and Hermine, Olivier, additional

Published
2022
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7. Reduced MDM2 and MDM4 Protein, but Not mRNA, Expression Is Associated with More Severe Disease in Acute Myeloid Leukemia (AML), Myelodysplastic Syndromes (MDS), and Chronic Myelomoncytic Leukemia (CMML)

Author

Salomao, Norman, primary, Maslah, Nabih, additional, Giulianelli, Anouk, additional, Drevon, Louis, additional, Aguinaga, Lorea, additional, Gu, Xiaolian, additional, Cassinat, Bruno, additional, Giraudier, Stephane, additional, Fenaux, Pierre, additional, and Fahraeus, Robin, additional

Published
2022
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8. USAID Associated with Myeloid Neoplasm and VEXAS Syndrome: Two Differential Diagnoses of Suspected Adult Onset Still’s Disease in Elderly Patients

Author

Delplanque, Marion, primary, Aouba, Achille, additional, Hirsch, Pierre, additional, Fenaux, Pierre, additional, Graveleau, Julie, additional, Malard, Florent, additional, Roos-Weil, Damien, additional, Belfeki, Nabil, additional, Drevon, Louis, additional, Oganesyan, Artem, additional, Groh, Matthieu, additional, Mahévas, Matthieu, additional, Razanamahery, Jerome, additional, Maigne, Gwenola, additional, Décamp, Matthieu, additional, Miranda, Sébastien, additional, Quemeneur, Thomas, additional, Rossignol, Julien, additional, Sailler, Laurent, additional, Sébert, Marie, additional, Terriou, Louis, additional, Sevoyan, Anna, additional, Hakobyan, Yervand, additional, Georgin-Lavialle, Sophie, additional, and Mekinian, Arsène, additional

Published
2021
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9. Revisiting Diagnostic performances of serum erythropoïetin level and JAK2 mutation for polycythemias: analysis of a cohort of 1090 patients with red cell mass measurement

Author

Maslah, Nabih, primary, Ravdan, Odonchimeg, additional, Drevon, Louis, additional, Verger, Emmanuelle, additional, Belkhodja, Célia, additional, Chomienne, Christine, additional, Cassinat, Bruno, additional, Kiladjian, Jean‐Jacques, additional, Giraudier, Stéphane, additional, and Schlageter, Marie‐Hélène, additional

Published
2021
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10. FLT3 Ligand Kinetic Profile Predicts Response to Treatment and Event-Free Survival (EFS) in Adults with High-Risk MDS/CMML Receiving CPX-351: A GFM Study

Author

Peterlin, Pierre, Gaschet, Joëlle, Turlure, Pascal, Gourin, Marie-Pierre, Dumas, Pierre-Yves, Thepot, Sylvain, Berceanu, Ana, Park, Sophie, Hospital, Marie Anne, Cluzeau, Thomas, Torregrosa-Diaz, Jose-Miguel, Drevon, Louis, Sapena, Rosa, Chermat, Fatiha, Dimicoli-Salazar, Sophie, Jullien, Maxime, Fenaux, Pierre, and Chevallier, Patrice

Published
2023
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11. Anemia and hemodilution: analysis of a single center cohort based on 2,858 red cell mass measurements

Author

Drevon, Louis, primary, Maslah, Nabih, additional, Soret-Dulphy, Juliette, additional, Dosquet, Christine, additional, Ravdan, Odno, additional, Vercellino, Laetitia, additional, Belkhodja, Celia, additional, Parquet, Nathalie, additional, Brignier, Anne C., additional, Schlageter, Marie-Helene, additional, Cassinat, Bruno, additional, Kiladjian, Jean-Jacques, additional, Chomienne, Christine, additional, and Giraudier, Stéphane, additional

Published
2021
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12. Revisiting Diagnostic performances of serum erythropoïetin level and JAK2 mutation for polycythemias: analysis of a cohort of 1090 patients with red cell mass measurement.

Author

Maslah, Nabih, Ravdan, Odonchimeg, Drevon, Louis, Verger, Emmanuelle, Belkhodja, Célia, Chomienne, Christine, Cassinat, Bruno, Kiladjian, Jean‐Jacques, Giraudier, Stéphane, and Schlageter, Marie‐Hélène

Subjects
ERYTHROCYTES, MASS measurement, ERYTHROPOIETIN receptors, COHORT analysis, POLYCYTHEMIA vera, ERYTHROPOIETIN
Abstract

Summary: We assessed the diagnostic performances of erythropoietin and JAK2 mutations in 1,090 patients with suspected polycythemia who were referred for red cell mass (RCM) measurement. In patients with a high haematocrit and/or haemoglobin level, a low erythropoietin level (<=3·3 mUI/ml) and JAK2 mutation showed comparable positive predictive value (PPV) for true polycythemia (RCM>=125%), 92·1% and 90% respectively. A very‐low erythropoietin level (<=1·99 mUI/ml) had a PPV of 100% for polycythemia vera (PV) diagnosis. We confirmed the correlations between RCM, erythropoietin and JAK2 variant allelic frequency in PV patients. This study prompts the need to revisit the role of EPO in PV diagnostic criteria. [ABSTRACT FROM AUTHOR]

Published
2022
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13. Syndromes myélodysplasiques avec trisomie 8 isolée : une forme fréquemment associée à des caractéristiques myéloprolifératives ?

Author

Drevon, Louis, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), and Pierre Fenaux

Subjects
Trisomie 8, MESH: Chromosome 8, trisomy, Syndromes myélodysplasiques, Myelodysplastic syndromes, Néoplasies myéloprolifératives, MESH: Myelodysplastic Syndromes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Myeloproliferative neoplasms
Abstract

Isolated trisomy 8 (+8) is a frequent cytogenetic abnormality in the myelodysplastic syndromes (MDS), but its characteristics are poorly reported. We performed a retrospective study of patients with isolated +8, classified or reclassified as MDS according to the WHO 2016 classification (excluding myelodysplastic syndromes/myeloproliferative neoplasms). Myeloproliferative (MP) features were defined by the repeated presence of one of the following: white blood count > 10.109/L, myelemia (presence of circulating immature granulocytes with a predominance of mature forms) > 2%, palpable splenomegaly. 138 patients were included, of whom 44.9% MDS-EB-1 or -2, 39.8% MDS-SLD or MDS-MLD, 10.9% MDS-RS and 4.3% MDS-U. MP features were present in 54 patients (39.1%): 28 at diagnosis, 26 acquired during evolution. The mean percentage of metaphases with +8 was 58.9% in the MP group, and 47.0% in the non-MP group (p = 0.043). MP forms had more EZH2 (33.3 vs. 12.0% in non-MP, p = 0.047), ASXL1 (66.7 vs. 42.3%, p = 0.048) and STAG2 mutations (77.8 vs. 21.7%, p = 0.006). Median event-free survival (EFS) and overall survival (OS) were 25 and 27 months for patients with MP features at diagnosis, versus 28 (p = 0.14) and 39 months (p = 0.085) for those without MP features, respectively. Among the 57 patients who received hypomethylating agent (HMA), OS was lower in MP cases (13 vs. 23 months in non-MP cases, p = 0.02). In conclusion, MP features are frequent in MDS with isolated +8. MP forms had more mutations of EZH2, ASXL1 and STAG2, responded poorly to HMA, and tended to have poorer survival than non-MP forms.; La trisomie 8 (+8) isolée est une anomalie cytogénétique fréquente dans les syndromes myélodysplasiques (SMD), mais ses caractéristiques sont peu rapportées. Nous avons réalisé une étude rétrospective auprès de patients avec une +8 isolée, classés ou reclassés en SMD selon la classification OMS 2016 (en excluant les SMD/néoplasies myéloprolifératives). Les caractéristiques myéloprolifératives (MP) étaient définies par la présence répétée de l'un des critères suivants : leucocytes > 10.109/L, myélémie > 2%, splénomégalie palpable. Ont été inclus 138 patients, dont 44,9% de SMD-EB-1 ou -2, 39,8% de SMD-SLD ou SMD-MLD, 10,9% de SMDRS et 4,3% de SMD-U. Des caractéristiques MP étaient présentes chez 54 patients (39,1 %) : 28 au diagnostic, 26 acquises au cours de l'évolution. En moyenne, le pourcentage de métaphases avec +8 était de 58,9% dans le groupe MP, et de 47,0% dans le groupe non MP (p = 0,043). Les formes MP avaient plus de mutations d’EZH2 (33,3 vs. 12,0 % chez les non MP, p = 0,047), d’ASXL1 (66,7 vs. 42,3 %, p = 0,048) et de STAG2 (77,8 vs. 21,7 %, p = 0,006). La survie sans évènement (EFS) et la survie globale (OS) médianes étaient respectivement de 25 et 27 mois pour les patients MP au diagnostic, contre 28 (p = 0,14) et 39 mois (p = 0,085) pour ceux non MP. Parmi les 57 patients ayant reçu un agent hypométhylant (HMA), l’OS était plus faible dans les cas MP (13 vs. 23 mois dans les cas non MP, p = 0,02). En conclusion, les caractéristiques MP sont fréquentes dans les SMD avec +8 isolée. Les formes MP présentaient plus de mutations d’EZH2, d’ASXL1 et de STAG2, répondaient moins bien aux HMA, et avaient tendance à avoir une survie plus faible que les formes non MP.

Published
2019

14. Synergistic effects of PRIMA-1Met (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia

Author

Maslah, Nabih, primary, Salomao, Norman, additional, Drevon, Louis, additional, Verger, Emmanuelle, additional, Partouche, Nicolas, additional, Ly, Pierre, additional, Aubin, Philippe, additional, Naoui, Nadia, additional, Schlageter, Marie-Helene, additional, Bally, Cecile, additional, Miekoutima, Elsa, additional, Rahmé, Ramy, additional, Lehmann-Che, Jacqueline, additional, Ades, Lionel, additional, Fenaux, Pierre, additional, Cassinat, Bruno, additional, and Giraudier, Stephane, additional

Published
2019
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15. Myelodysplastic syndrome (MDS) with isolated trisomy 8: a type of MDS frequently associated with myeloproliferative features? A report by the Groupe Francophone des Myélodysplasies

Author

Drevon, Louis, primary, Marceau, Alice, additional, Maarek, Odile, additional, Cuccuini, Wendy, additional, Clappier, Emmanuelle, additional, Eclache, Virginie, additional, Cluzeau, Thomas, additional, Richez, Valentine, additional, Berkaoui, Inès, additional, Dimicoli‐Salazar, Sophie, additional, Bidet, Audrey, additional, Vial, Jean‐Philippe, additional, Park, Sophie, additional, Vieira Dos Santos, Christina, additional, Kaphan, Eléonore, additional, Berthon, Céline, additional, Stamatoullas, Aspasia, additional, Delhommeau, François, additional, Abermil, Nassera, additional, Braun, Thorsten, additional, Sapena, Rosa, additional, Lusina, Daniel, additional, Renneville, Aline, additional, Adès, Lionel, additional, Raynaud, Sophie, additional, and Fenaux, Pierre, additional

Published
2018
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16. Gastrointestinal Behcet's-like disease with myelodysplastic neoplasms with trisomy 8: a French case series and literature review.

Author

Wesner, Nadege, Drevon, Louis, Guedon, Alexis, Fraison, Jean Baptiste, Terrier, Benjamin, Trad, Salim, Kahn, Jean Emmanuel, Aouba, Achille, Gillard, Jerome, Ponsoye, Matthieu, Hanslik, Thomas, Gourguechon, Clement, Liozon, Eric, Laribi, Kamel, Rossignol, Julien, Hermine, Olivier, Seksik, Philippe, Adès, Lionel, Carrat, Fabrice, and Fenaux, Pierre

Subjects
*CROHN'S disease, *BEHCET'S disease, *GASTROINTESTINAL diseases, *JOINT pain, *LITERATURE reviews, *CANCER
Abstract

We report the 11 cases of +8-MDS/MPN associated with Behcet's-like syndrome and compare them with Behcet's disease and Crohn's disease, pool with literature cases for analysis. Data for patients with +8-MDS/MPN and Behçet's-like syndrome were collected from MINHEMON. Eleven patients had Behcet's-like syndrome and +8-MDS/MPN (median age 75 years [IQR 65–87]; M/F ratio 0.8). MDS and Behcet's-like syndrome were diagnosed at the same time (7/11, 64%). By comparison with 63 patients with idiopathic Behcet's disease without associated MDS, those with Behcet's-like syndrome and +8-MDS/MPN were older (median 75 vs 48 years; p =.0003) and had less pseudofolliculitis (11% vs 62%; p =.0045) and ocular impairment (0% vs 52%; p =.0008), but more frequent gastrointestinal involvement (60% vs 13%; p =.0005). By comparison with Crohn's disease, 39 patients with Behcet's-like syndrome and +8-MDS/MPN were significantly older (median 72 [53–78] vs 36 [27–45] years; p =.0002) and more frequently had oral aphtosis (97% vs 5%, p <.0001), skin features (50% vs 10%, p =.0005) and arthralgia (63% vs 20%, p =.03). Median survival did not differ between patients with Behcet's-like syndrome and +8-MDS/MPN and those with +8-MDS/MPN (n = 103) (47 vs 34 months, p =.61). AML-free survival did not differ between patients with MDS/MPN with and without Behcet's-like syndrome (p =.29). MDS/MPN with trisomy 8 can be associated with particular phenotype of ulcerative digestive disease resembling Behcet's or Crohn's disease and should be considered a single disease. [ABSTRACT FROM AUTHOR]

Published
2019
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17. Inflammatory disorders associated with trisomy 8‐myelodysplastic syndromes: French retrospective case‐control study.

Author

Wesner, Nadege, Drevon, Louis, Guedon, Alexis, Fraison, Jean Baptiste, Trad, Salim, Kahn, Jean Emmanuel, Aouba, Achille, Gillard, Jerome, Ponsoye, Matthieu, Hanslik, Thomas, Gourguechon, Clement, Liozon, Eric, Laribi, Kamel, Rossignol, Julien, Hermine, Olivier, Adès, Lionel, Carrat, Fabrice, Fenaux, Pierre, Mekinian, Arsene, and Fain, Olivier

Subjects
*MYELODYSPLASTIC syndromes, *MYELOPROLIFERATIVE neoplasms, *GENETICS of autoimmune diseases, *IMMUNOLOGY of inflammation, *COMMUNICABLE disease immunology
Abstract

Objective: We report cases of myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) with trisomy 8 associated with inflammatory and autoimmune diseases (IADs). Method: Data for 21 patients with trisomy 8‐MDS/MPN and IADs were analyzed and compared to 103 patients with trisomy 8‐MDS/MPN without IADs. Results: The median age of MDS/MPN patients with IADs was 67 [59‐80]. The IADs were Behçet's‐like disease in 11 (52%) patients, inflammatory arthritis in 4 (19%) and Sjögren's syndrome, autoimmune hemolytic anemia, aseptic abscess, periarteritis nodosa, Sweet's syndrome and unclassified vasculitis in one patient each. Overall, 17/21 (81%) patients with IADs received treatment (88% with steroids), with complete and partial response in 7/17 (35%) and 8/17 (47%), respectively. The effect of MDS treatment on IADs could be assessed in seven patients receiving azacytidine: five achieved remission and two partial response. As compared with the 103 trisomy 8‐MDS/MPN cases without IADs, those with IADs were more often non‐European (P = 0.005) and had poor karyotype (P < 0.001). We found no difference in overall survival or acute myeloid leukemia progression between trisomy 8‐associated MDS/MPN with and without IADs. Conclusion: The spectrum of IADs associated with trisomy 8‐positive MDS/MPN is dominated by Behçet's‐like disease. Steroid therapy is effective, but mostly sparing therapies are necessary. Azacytidine could be an effective alternative. [ABSTRACT FROM AUTHOR]

Published
2019
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18. MDS with Isolated Trisomy 8. a Type of MDS Frequently Associated with Myeloproliferative Features? A Report from the GFM

Author

Drevon, Louis, primary, Marceau, Alice, additional, Eclache, Virginie, additional, Raynaud, S. Dominique, additional, Richez, Valentine, additional, Berkaoui, Inès, additional, Maarek, Odile, additional, Cuccuini, Wendy, additional, Lusina, Daniel, additional, Berthon, Celine, additional, Dimicoli-Salazar, Sophie, additional, Bidet, Audrey, additional, Vial, Jean-Philippe, additional, Park, Sophie, additional, Stamatoullas, Aspasia, additional, Vieira Dos Santos, Christina, additional, Braun, Thorsten, additional, Sapena, Rosa, additional, Renneville, Aline, additional, Ades, Lionel, additional, and Fenaux, Pierre, additional

Published
2015
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19. In silicoand Functional Studies for Classification of EPAS1/HIF2AGenetic Variants Identified in Patients with Erythrocytosis

Author

Karaghiannis, Valéna, Maric, Darko, Garrec, Céline, Maaziz, Nada, Buffet, Alexandre, Antunes, Vincent, le Roy, Amandine, Airaud, Fabrice, Aral, Bernard, Schmitt, Loic, Corbineau, Sébastien, Mansour-Hendili, Lamisse, Lesieur, Valentine, Rimbert, Antoine, Laporte, Fabien, Delamare, Marine, Bezieau, Stephane, Cassinat, Bruno, Galactéros, Frédéric, Gimenez-Roqueplo, Anne-Paule, Burnichon, Nelly, Cario, Holger, Wijk, Richard van, Bento, Celeste, Blouet, Anaise, Bouteloup, Juliette, Boyer perrard, Françoise, Bruce, Aisha Aiko, Cayssials, Emilie, Casadevall, Nicole, Cherel, Brieuc, Couec, Marielaure, Drevon, Louis, Dumesnil, Cecile, Lamy De La Chapelle, Thierry, Gambart, Marion, Garcon, Loic, Granel, Brigitte, Hirsch, Pierre, Lahary, Agnès, Mejri, Amira, Meunier, Sandrine, Nicolini, Franck E., Raffoux, Emmanuel, Ranta, Dana, Schleinitz, Nicolas, Valentin, Jean Baptiste, Wemeau, Mathieu, Girodon, Francois, Hoogewijs, David, Gardie, Betty, and Hermine, Olivier

Published
2022
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20. FLT3 ligand kinetic profile predicts response to treatment in patients with high-risk myelodysplastic syndrome / chronic myelomonocytic leukemia receiving CPX-351: a study from the Groupe Francophone des Myélodysplasies.

Author

Peterlin P, Gaschet J, Turlure P, Gourin MP, Dumas PY, Thepot S, Berceanu A, Park S, Hospital MA, Cluzeau T, Torregrosa-Diaz JM, Drevon L, Sapena R, Chermat F, Ades L, Dimicoli-Salazar S, Jullien M, Fenaux P, and Chevallier P

Abstract

Not available.

Published
2024
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21. Reduced murine double minute 2 and 4 protein, but not messenger RNA, expression is associated with more severe disease in myelodysplastic syndromes and acute myeloblastic leukaemia.

Author

Salomao N, Maslah N, Giulianelli A, Drevon L, Aguinaga L, Gu X, Cassinat B, Giraudier S, Fenaux P, and Fahraeus R

Subjects
Humans, Mice, Animals, Proto-Oncogene Proteins c-mdm2 genetics, Proto-Oncogene Proteins c-mdm2 metabolism, Proto-Oncogene Proteins genetics, Tumor Suppressor Protein p53 genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics
Abstract

The human homologues of murine double minute 2 (MDM2) and 4 (MDM4) negatively regulate p53 tumour suppressor activity and are reported to be frequently overexpressed in human malignancies, prompting clinical trials with drugs that prevent interactions between MDM2/MDM4 and p53. Bone marrow samples from 111 patients with acute myeloblastic leukaemia, myelodysplastic syndrome or chronic myelomonocytic leukaemia were examined for protein (fluorescence-activated cell sorting) and messenger RNA (mRNA) expression (quantitative polymerase chain reaction) of MDM2, MDM4 and tumour protein p53 (TP53). Low protein expression of MDM2 and MDM4 was observed in immature cells from patients with excess of marrow blasts (>5%) compared with CD34 + /CD45 low cells from healthy donors and patients without excess of marrow blasts (<5%). The mRNA levels were indistinguishable in all samples examined regardless of disease status or blast levels. Low MDM2 and MDM4 protein expression were correlated with poor survival. These data show a poor correlation between mRNA and protein expression levels, suggesting that quantitative flow cytometry analysis of protein expression levels should be used to predict and validate the efficacy of MDM2 and MDM4 inhibitors. These findings show that advanced disease is associated with reduced MDM2 and MDM4 protein expression and indicate that the utility of MDM2 and MDM4 inhibitors may have to be reconsidered in the treatment of advanced myeloid malignancies., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Published
2023
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22. Synergistic effects of PRIMA-1 Met (APR-246) and 5-azacitidine in TP53 -mutated myelodysplastic syndromes and acute myeloid leukemia.

Author

Maslah N, Salomao N, Drevon L, Verger E, Partouche N, Ly P, Aubin P, Naoui N, Schlageter MH, Bally C, Miekoutima E, Rahmé R, Lehmann-Che J, Ades L, Fenaux P, Cassinat B, and Giraudier S

Subjects
Aza Compounds, Azacitidine pharmacology, Bridged Bicyclo Compounds, Heterocyclic, Humans, Quinuclidines, Tumor Suppressor Protein p53 genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics
Abstract

Myelodysplastic syndromes and acute myeloid leukemia with TP53 mutations are characterized by frequent relapses, poor or short responses, and poor survival with the currently available therapies including chemotherapy and 5-azacitidine (AZA). PRIMA-1 Met (APR-246,APR) is a methylated derivative of PRIMA-1, which induces apoptosis in human tumor cells through restoration of the transcriptional transactivation function of mutant p53. Here we show that low doses of APR on its own or in combination with AZA reactivate the p53 pathway and induce an apoptosis program. Functionally, we demonstrate that APR exerts these activities on its own and that it synergizes with AZA in TP53 -mutated myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) cell lines and in TP53 -mutated primary cells from MDS/AML patients. Low doses of APR on its own or in combination with AZA also show significant efficacy in vivo Lastly, using transcriptomic analysis, we found that the APR + AZA synergy was mediated by downregulation of the FLT3 pathway in drug-treated cells. Activation of the FLT3 pathway by FLT3 ligand reversed the inhibition of cell proliferation by APR + AZA. These data suggest that TP53 -mutated MDS/AML may be better targeted by the addition of APR-246 to conventional treatments., (Copyright© 2020 Ferrata Storti Foundation.)

Published
2020
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