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PhD POSITION TO STUDY THE TUMOR MICROENVIRONMENT OF ACUTE MYELOID LEUKEMIA

Host team & institute: BENAJIBA team – Identification and targeting of extrinsic regulators of myeloid malignancies – INSERM U944 – Saint-Louis Research Institute

                  Website: https://gencelldis.fr/l-benajiba-team/

                  Address: Hôpital Saint-Louis – 16, rue de la grange aux belles, 75010, Paris.

Saint-Louis Research Institute was created in 1958 by Jean Bernard and Jean Dausset (Nobel Prize), aiming to achieve excellence in research and teaching, in the fields of hematology, oncology, cell biology, immunology, virology, genetics and therapeutic biotechnologies. Our research institute is located in the center of Paris within the Saint-Louis campus, and benefits from a close relationship and collaboration with Saint-Louis hospital. The institute is affiliated to the doctoral school of “Hematology, Oncology & Biotherapies” and hosts the “European School of Hematology”, thus participating to the training of over 2000 researchers and clinicians every year. Since 2024, Saint-Louis Research Institute is also the home of the ambitious “Leukemia Institute THEMA” (IHU), which seeks to develop novel approaches to cure leukemia and associated disorders.

Our research unit (UMR U944: genomes, cellular biology & therapeutics), has an internationally recognized research program with world-renowned leukemia researchers, such as Jean Soulier, Hugues de Thé and Alexandre Puissant. Consequently, intellectual interactions among our department members are fostered by a number of weekly research seminars. Our research unit is composed of 6 groups whose research encompasses a broad spectrum of fields, including basic virology, cell biology, cancer genomics, cancer biology and leukemia research, yeast biology, functional studies of post-translational modifications and chromosome biology. Our team is focused on identification and targeting of extrinsic and epigenetic regulators of myeloid malignancies, and is currently composed of 3 principal investigators, 2 associated clinicians, 1 lab manager, 2 bio-informaticians, 3 research technicians, 2 post-doctoral fellows, 4 PhD students and 3 Master students. Most of the studies carried out by our team bridge several of those fields and have implications in translational research, together with the clinical groups of Saint-Louis hospital. The team works in close partnership with Saint-Louis Hospital Clinical Investigations Center (INSERM-CIC 1427) to accelerate the clinical translation of our lab discoveries. Our team also benefits from a privileged access to primary patient samples and a large variety of institutional core facilities, including a fully equipped animal facility, a flow cytometry facility, a sequencing facility, and an imaging facility.

Available position: A three years fully-funded PhD position (possible 1 year extension) is open in the team led by Dr Lina BENAJIBA, a physician-scientist focusing on target identification and drug discovery in Acute Myeloid Leukemia. Starting date should be between November 2024 and December 2024.

We are looking for a highly motivated and dynamic student wishing to complete his doctoral training in a young and international ERC starting and ATIP-Avenir team, hosted by an internationally renowned INSERM Unit. The candidate must appreciate teamwork, have good interpersonal skills and be rigorous and organized in his/her work. Experience in molecular/cellular biology is required. Experience in murine models would be an asset. Applicants should hold a Master degree in Biochemistry, Cellular Biology, Molecular Biology, Oncology, Hematology or related disciplines.

Project description: Our team develops translational research strategies focused on the identification of druggable oncogenic targets to pave the road for successful acute myeloid leukemia (AML) treatment. The PhD student will seek to dissect the key role of the bone marrow (BM) niche in AML drug resistance, aiming ultimately to develop concomitant “seeds” and “soil” curative therapeutic strategies to improve patients’ prognosis. Novel niche-hematopoietic crosstalk-induced dependencies will be unraveled using transcriptomic technologies combined to high-throughput functional screening methods. Pre-leukemic in vivo BM-AML organoid models will be used to shed light on the mechanistic underpinnings of the newly identified niche-driven drug resistance mechanisms.

Selected publications:

1. Kelly LM, Rutter JC, Lin KH, Ling F, Duchmann M, Latour E, Arang N, Pasquer H, Ho Nhat D, Charles J, Killarney ST, Ang HX, Namor F, Culeux C, Lombard B, Loew D, Swaney DL, Krogan NJ, Brunel L, Carretero É, Verdié P, Amblard M, Fodil S, Huynh T, Sebert M, Adès L, Raffoux E, Fenouille N, Itzykson R, Lobry C, Benajiba L, Forget A, Martin AR, Wood KC, Puissant A. Targeting a lineage-specific PI3Kɣ-Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule. Nature Cancer. 2024 May 30. IF: 23.177

2. Lin KH, Rutter JC, Xie A, Killarney ST, Vaganay C, Benaksas C, Ling F, Sodaro G, Meslin PA, Bassil CF, Fenouille N, Hoj J, Washart R, Ang HX, Cerda-Smith C, Chaintreuil P, Jacquel A, Auberger P, Forget A, Itzykson R, Lu M, Lin J, Pierobon M, Sheng Z, Li X, Chilkoti A, Owzar K, Rizzieri DA, Pardee TS, Benajiba L, Petricoin E, Puissant A, Wood KC. P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia. Nature Cancer. 2022 Jul;3(7):837-851. IF: 23.177

3. Roux B, Vaganay C, Vargas JD, Alexe G, Benaksas C, Pardieu B, Fenouille N, Ellegast JM, Malolepsza E, Ling F, Sodaro G, Ross L, Pikman Y, Conway AS, Tang Y, Wu T, Anderson DJ, Le Moigne R, Zhou HJ, Luciano F, Hartigan CR, Galinsky I, DeAngelo DJ, Stone RM, Auberger P, Schenone M, Carr SA, Guirouilh-Barbat J, Lopez B, Khaled M, Lage K, Hermine O, Hemann MT, Puissant A, Stegmaier K, Benajiba L. Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor. Science Translational Medicine. 2021 Mar 31;13(587):eabg1168. IF: 17.956

4. Marcault C, Zhao LP, Maslah N, Verger E, Daltro De Oliveira R, Soret-Dulphy J, Gauthier N, Roux B, Clappier E, Parquet N, Dosquet C, Rea D, Zini JM, Vainchenker W, Raffoux E, Giraudier S, Kiladjian JJ, Cassinat B, Benajiba L. Impact of NFE2 mutations on AML transformation and overall survival in patients with myeloproliferative neoplasms (MPN). Blood. 2021 Nov 25;138(21):2142-2148. IF: 23.629

5. Benajiba L*, Wagner FF*, Campbell AJ, Weiwer M, Sacher JR, Gale JP, Ross L, Puissant A, Alexe G, Conway A, Back M, Pikman Y, Galinsky I, DeAngelo DJ, Stone RM, Kaya T, Shi X, Robers MB, Machleidt T, Wilkinson J, Hermine O, Kung A, Stein AJ, Lakshminarasimhan D, Hemann MT, Scolnick E, Zhang YL, Pan JQ, Stegmaier K and Holson EB. Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia. Science Translational Medicine. 2018 Mar 7;10(431):eaam8460. IF 17.2

Application & Contact: Applications must be sent to lina.benajiba@inserm.fr as a single PDF file including:

–        Cover letter explaining the candidate’s interest in joining the lab and his/her future career development expectations (max 1 page).

–        Curriculum Vitae including academic track, main technical skills, main past achievements and scientific productions.

–        Contact details of two past supervisors who can be contacted for recommendation letters.