Lionel Blanc, PhD

Associate Investigator, Laboratory of Developmental Erythropoiesis,
Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research

Associate Professor, Molecular Medicine and Pediatrics, Hofstra Northwell School of Medicine

Phone: (516) 562-1507
Email: lblanc@northwell.edu

About the Investigator

Dr. Blanc received his PhD in Molecular Medicine from the university of Montpellier in 2008. He then moved to New York to do his postdoctoral training at the New York Blood Center in the Red Cell Laboratory and the Mammalian Genetics Laboratory, under the essential mentoring of Drs. Mohandas Narla and Luanne Peters respectively. After three years and a half spent at the New York Blood center, Dr. Blanc joined the Northwell Health Department of Pediatrics Hematology/Oncology in 2012 as a postdoctoral fellow first. Shortly after, he became an Assistant Investigator and an Assistant Professor of Molecular Medicine and Pediatrics and established the Laboratory of Developmental Erythropoiesis. The two main axes of research are: (i) developmental erythropoiesis and its impairment in pathological conditions and (ii) cancer predisposition in children with Diamond Blackfan anemia. In 2014, Dr. Blanc received the Allied World Career Development Award from the St. Baldrick’s Foundation in order to study this osteogenic sarcoma development in these children.

Dr. Blanc has established numerous collaboration both nationally and internationally, and also served as ad-hoc member on NIH study section as early career reviewer.

Finally, Dr. Blanc is involved in the teaching of the Hematology course for the first-year students at the Hoftra-Northwell School of Medicine, and notably give them a lecture on the hematopoietic stem cell and on the structure of the red cell membrane. He is also involved in the critical reading course offered to the MD-PhD students. He is currently mentoring two successful MD/PhD students.

Research Focus

Pathophysiology of Erythropoiesis

Anemia affects 1.6 billion people worldwide and as such represents a global economic burden. Many of the anemic phenotypes originate from defects in red cell production (i.e. erythropoiesis). One of the major goals of our laboratory is to understand how erythropoiesis is regulated and how perturbations in this program lead to anemia. 3 main projects are actively pursued in the lab:

1) Functional Studies of the RASA3/Ras Signaling Pathway During Mammalian Erythropoiesis

In the mouse model scat (severe combined anemia and thrombocytopenia), a missense mutation in Rasa3 leads to the anemia phenotype.

RASA3 is a Ras-GTPase activating protein that negatively regulates Ras. Using primary cells in an in vitro culture system, we are investigating the molecular pathways that lead to a defect of erythropoiesis and hemoglobinization in the scat mouse model.  Furthermore, the role of the RASA3/Ras axis is also assessed during the more mature stages of erythropoiesis.

At the erythrocyte stage, we are interested in defining the role of Ras in the maintenance of red cell membrane integrity with the use of biophysical and biochemical techniques.

Finally, we are using RASA3 knockdown approaches in CD34+ differentiating cells to expand this paradigm to humans and are developing pilot studies to decipher the putative role of this signaling pathway in patients with bone marrow failure of unknown origin.

Delineating the role of the RASA3/Ras axis in red cell signaling during erythroid differentiation will give new insights into red cell physiology and will significantly improve our understanding of bone marrow failure syndromes and may provide new therapeutic targets.

2) Transcriptional Reprograming of Adult Erythroid Progenitors and Implications for the Treatment of b-Hemoglobinopathies

The only FDA-approved drug for the treatment of sickle cell disease is hydroxyurea. Hydroxyurea leads to the production of fetal hemoglobin, which is beneficial for patients affected by sickle cell disease. However, hydroxyurea is modestly effective, and there is a need for the development of additional drugs. We recently published part of the mechanism of action of pomalidomide during human erythropoiesis (Dulmovits et al. Blood, 2016, and editorial). These studies have direct clinical relevance since pomalidomide reactivates fetal hemoglobin production in hematopoietic progenitors from both normal and sickle cell disease patients and is already FDA-approved for the treatment of multiple myeloma (click here for press release). We are now investigating how pomalidomide coordinately downregulates multiple γ-globin gene repressors.

3) Erythropoiesis in Sepsis Survivors

Anemia of inflammation is extensively studied, and tremendous progress has been made towards our understanding of this condition. However, much less is known about anemia in sepsis survivors. In collaboration with Drs. Kevin Tracey and Betty Diamond, we conducted a study in murine sepsis survivors and found that HMGB1, a known mediator of inflammation in sepsis survivors, is also involved in the development of the anemia observed in these animals (Valdes-Ferrer et al. Molecular Medicine, 2016). We are now translating these findings into human studies, and also started investigated the role of the macrophage in the erythroblastic island.

Skeletal Defects and predisposition to osteogenic sarcoma in Diamond Blackfan anemia

Diamond Blackfan Anemia (DBA) is one of the rare, inherited bone marrow failure syndromes, mostly observed in children and usually presenting within the first year of life. DBA is characterized by a dramatic decrease in production of red blood cells and short stature. In addition, patients affected by this condition are more prone to develop cancers, notably a cancer of the bone known as osteogenic sarcoma. Osteogenic sarcoma is in fact the most common bone tumor. Even though osteogenic sarcoma is a relatively common pediatric solid tumor, very little is known about how and why it develops. If the disease is localized, the long-term survival rate is 70 to 75%. However, if the disease is metastatic (usually to the lungs or other bones) at diagnosis, the long-term survival rate is only 30%. Unfortunately, these statistics have not changed in decades. Existing therapies include complex and often function-limiting surgery and aggressive chemotherapy. There is, therefore, a strong need to better understand this form of childhood cancer, in order to improve existing treatments and increase cure rates. We are investigating the mechanism by which this cancer develops in children with DBA. Specifically, we are exploring the hypothesis that this cancer can result from genetic mutations in ribosomal proteins.

Lab Members

blanc-lab-team

Jeffrey M. Lipton, MD, PhD
Investigator
Research: In addition to his specific research interests, Dr. Lipton is mentoring Dr. Blanc on the osteogenic sarcoma predisposition in Diamond Blackfan anemia project.
Email: Jlipton@northwell.edu

Julien Papoin, MS
Research Associate
Research: Julien is managing the lab and is conducting experiments focused on the role of RASA3 during mammalian erythropoiesis and on the enucleation of the erythroblast.
Email: Jpapoin@northwell.edu

Brian M. Dulmovits, MS
Medical Student / PhD Student
2014 American Society of Hematology Physician Scientist Career Development Award Recipient
Research: Brian studies the transcriptional and developmental reprograming of adult hematopoietic progenitors. Brian is also involved in the erythropoiesis in sepsis survivors project and the osteosarcoma project.
Email: Bdulmovits@northwell.edu

Jimmy Hom, BA
MD/PhD Student
Research: Jimmy studies the skeletal defects and predisposition to osteogenic sarcoma in children with Diamond Blackfan anemia. He is also involved in the erythropoiesis in sepsis project, in particular for the cross-talk between macrophages and developing erythroblasts in the erythroblastic island.
Email: Jhom2@northwell.edu

External collaborators

Luanne L. Peters, PhD
The Jackson Laboratory, Bar Harbor, ME

Michel Vidal, PhD
Universite Montpellier II, Montpellier, France
Education

Montpellier II University, Montpellier, France
Degree: BA
2002
Field of Study: Biochemistry and Cell Biology

Montpellier II University, Montpellier, France
Degree: MS
2004
Field of Study: Cellular and Molecular Endocrinology

Montpellier II University, Montpellier, France
Degree: PhD
2008
Field of Study: Biochemistry and Cell Biology

New York Blood Center, New York, NY
Degree: Postdoctoral
2012
Field of Study: Red Cell Physiology Erythropoiesis

The Feinstein Institute for Medical Research, Manhasset, NY
Degree: Postdoctoral
2012
Field of Study: Bone Marrow Failures

Honors and Awards

2015 Early Career Reviewer, Center for Scientific Review, NIH
2011 American Society of Hematology. Abstract Achievement Award
2004-2008 Montpellier II University, France. Competitive Teaching Fellowship Award from the french government.

Publications
  1. Valdés-Ferrer, S., Papoin, J., Dancho, M. E., Olofsson, P. S., Li, J., Lipton, J. M., Avancena, P., Yang, H., Zou, Y., Chavan, S., Volpe, B. T., Gardenghi, S., Rivella, S., Diamond, B., Andersson, U., Steinberg, B.M., Blanc, L.*, and Tracey, K. J.* (2016). “HMGB1 mediates anemia of inflammation in murine sepsis survivors.” Molecular Medicine, In Press. *Equal contributions.
  2. Dulmovits, B. M., Appiah-Kubi, A. O, Papoin, J., Hale, J., He, M., Al-Abed, Y., Didier, S., Gould, M., Husain-Krautter, S., Singh, S. A., Chan, K. W. H., Vlachos, A., Allen, S. L., Taylor, N., Marambaud, P., An, X., Gallagher, P. G., Mohandas, N., Lipton, J. M., Liu, J. M., and Blanc, L. “Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors.” Blood, 127(11):1481-1492.
  3. Blanc, L., Papoin, J., Debnath, G., Vidal, M., Amson, R., Telerman,A., An, X., and Mohandas, N. (2015). “Abnormal erythroid maturation leads to microcytic anemia in the TSAP6/Steap3 null mouse model.” American Journal of Hematology, Mar; 90(3):235-41.
  4. Vlachos, A., Farrar, J. E., Atsidaftos, E., Muir, E., Narla, A., Markello, T. C., Singh, S. A., Landowski, M., Gazda, H. T., Blanc, L., Liu, J. M., Ellis, S. R., Arceci, R. J., Ebert, B. L., Bodine, D. M., and Lipton J. M. (2013). “Diminutive somatic deletions in the 5q region lead to a phenotype atypical of classical 5q- syndrome.” Blood, Oct 3; 122(14):2487-90.
  5. Blanc, L., Ciciotte, S. L., Gwynn, B., Hildick-Smith, G. J., Pierce, E. L., Soltis, K. A., Cooney, J. D., Paw, B. H., and Peters, L. L. (2012).  “Critical function for the Ras-GTPase activating protein RASA3 in vertebrate erythropoiesis and megakaryopoiesis.” PNAS, 109(30):12099-104 PMC3409772
  6. Blanc, L., Salomao, M., Guo, X., An, X., Gratzer, W., and Mohandas, N. (2010). “Control of erythrocyte membrane-skeletal cohesion by the spectrin-membrane linkage.” Biochemistry, 49(21):4516-23. NIHMS202150
  7. Barres, C., Blanc, L., Bette-Bobillo, P., Andre, S., Mamoun, R., Gabius, H. J., and Vidal, M. (2010). “Galectin-5 is bound onto the surface of rat reticulocyte exosomes and modulates vesicle uptake by macrophages.” Blood, 115(3):696-705.
  8. Blanc, L., Liu, J., Vidal, M., Chasis, J. A., An, X., and Mohandas, N. (2009). “The water channel aquaporin-1 partitions into exosomes during reticulocyte maturation: implication for the regulation of cell volume.” Blood, 114(18):3928-3934. PMC2773486
  9. Montel Hagen, A., Blanc, L., Jaquet, C., Vidal, M., Sitbon, M., and Taylor, N. (2008). “The Glut1 and Glut4 glucose transporters are differentially expressed during perinatal and postnatal erythropoiesis.” Blood, 112(12):4729-38.
  10. Blanc, L., Barres, C., Bette-Bobillo, P., and Vidal, M. (2007). “Reticulocyte-secreted exosomes bind natural IgM antibodies : Involvement of a ROS-activatable endosomal iPLA2.” Blood, 110(9):3407-16.

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