Emmanuel Olivier

Albert Einstein College of Medicine

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Eric E. Bouhassira

Albert Einstein College of Medicine

Caihong Qiu

Affiliated Hospital of Guilin Medical College

Joanne C. Mountford

Scottish National Blood Transfusion Service

Zi Yan

Albert Einstein College of Medicine

Shouping Zhang

Henan Institute of Science and Technology

Emmanuelle Soury

Inserm

Jean‐Philippe Salier

Université de Rouen Normandie

Kai Wang

University of Electronic Science and Technology of China

Karl Roberts

Albert Einstein College of Medicine

Eirini P. Papapetrou

Icahn School of Medicine at Mount Sinai

Cooperative Institutions

Inserm

Albert Einstein College of Medicine

National Institutes of Health

Centre National de la Recherche Scientifique

Sorbonne Université

Assistance Publique – Hôpitaux de Paris

Université Paris Cité

The University of Texas MD Anderson Cancer Center

Icahn School of Medicine at Mount Sinai

National Heart Lung and Blood Institute

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RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax

Nature (2024)

Junya Sango Saul Carcamo Maria Sirenko Abhishek Maiti Hager Mansour

Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukaemia, upon progression or relapsed/refractory disease1–6. Here, by using human leukaemogenesis models, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte–monocyte progenitors) harbouring previously acquired driver mutations, showing that advanced leukaemic clones can originate from a different cell type in the haematopoietic hierarchy than ancestral clones. Furthermore, we demonstrate that RAS-mutant leukaemia stem cells (LSCs) give rise to monocytic disease, as observed frequently in patients with poor responses to treatment with the BCL2 inhibitor venetoclax. We show that this is because RAS-mutant LSCs, in contrast to RAS-wild-type LSCs, have altered BCL2 family gene expression and are resistant to venetoclax, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver shapes the non-genetic cellular hierarchy of acute myeloid leukaemia by imposing a specific LSC target cell restriction and critically affects therapeutic outcomes in patients. We find that RAS-mutant leukaemia stem cells are resistant to venetoclax, driving clinical resistance and relapse with monocytic features.

Venetoclax

10.1038/s41586-024-08137-x

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Novel, High-Yield Red Blood Cell Production Methods from CD34-Positive Cells Derived from Human Embryonic Stem, Yolk Sac, Fetal Liver, Cord Blood, and Peripheral Blood

Stem Cells Translational Medicine (2012)

Emmanuel Olivier Caihong Qiu Eric E. Bouhassira

Abstract The current supply of red blood cells expressing rare blood groups is not sufficient to cover all the existing transfusion needs for chronically transfused patients, such as sickle cell disease homozygous carriers, because of alloimmunization. In vitro production of cultured red blood cells is slowly emerging as a possible complement to the existing collection-based red blood cell procurement system. The yield of cultured red blood cells can theoretically be maximized by amplifying the stem, progenitor, or precursor compartment. Here, we combined methods designed to expand these three compartments to optimize the yield of cultured red blood cells and found that exposing CD34+ cells to a short pulse of cytokines favorable for erythroid differentiation prior to stem cell expansion followed by progenitor expansion produced the highest yield of erythroid cells. This novel serum-free red blood cell production protocol was efficient on CD34+ cells derived from human embryonic stem cells, 6–8-week yolk sacs, 16–18-week fetal livers, cord blood, and peripheral blood. The yields of cells obtained with these new protocols were larger by an order of magnitude than the yields observed previously. Globin expression analysis by high-performance liquid chromatography revealed that these expansion protocols generally yielded red blood cells that expressed a globin profile similar to that expected for the developmental age of the CD34+ cells.

Cord blood

Placenta cord banking

Yolk

10.5966/sctm.2012-0059

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Fetuin-B, a second member of the fetuin family in mammals

Biochemical Journal (2000)

Emmanuel Olivier Emmanuelle Soury Philippe Ruminy Annie Husson Françoise Parmentier

A set of orthologous plasma proteins found in human, sheep, pig, cow and rodents, now collectively designated fetuin-A, constitutes the fetuin family. Fetuin-A has been identified as a major protein during fetal life and is also involved in important functions such as inhibition of the insulin receptor tyrosine kinase activity, protease inhibitory activities and development-associated regulation of calcium metabolism and osteogenesis. Furthermore, fetuin-A is a key partner in the recovery phase of an acute inflammatory response. We now describe a second protein of the fetuin family, called fetuin-B, which is found at least in human and rodents. On grounds of domain homology, overall conservation of cysteine residues and chromosomal assignments of the corresponding genes in these species, fetuin-B is unambiguously a paralogue of fetuin-A. Yet, fetuin-A and fetuin-B exhibit significant differences at the amino acid sequence level, notably including variations with respect to the archetypal fetuin-specific signature. Differences and similarities in terms of gene regulation were also observed. Indeed, studies performed during development in rat and mouse showed for the first time high expression of a member of the fetuin family in adulthood, as shown with the fetuin-B mRNA in rat. However, like its fetuin-A counterpart, the fetuin-B mRNA level is down-regulated during the acute phase of experimentally induced inflammation in rat.

Fetuin

10.1042/bj3500589

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Citations (136)

Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection Can Be the Best Therapeutic Option in Severely Immunocompromised Patients Depending on a Case-by-Case Assessment of the Benefit-to-Risk Ratio

Gastroenterology (2024)

Nicolas Benech Nadim Cassir Tatiana Galperine Laurent Alric Julien Scanzi

Clostridioides

Fecal bacteriotherapy

10.1053/j.gastro.2024.04.022

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Citations (1)

2012 – N/KRAS-MUTANT AML LSCS ORIGINATE FROM COMMITTED MYELOMONOCYTIC PROGENITORS AND DRIVE CLINICAL RESISTANCE TO VENETOCLAX

Experimental Hematology (2024)

Junya Sango Saul Carcamo Maria Sirenko Abhishek Maiti Hager Mansour

Venetoclax

10.1016/j.exphem.2024.104569

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Differentiation of Human Embryonic Stem Cells into Bipotent Mesenchymal Stem Cells

Stem Cells (2006)

Emmanuel Olivier Anne C. Rybicki Eric E. Bouhassira

Mesenchymal stem cells (MSCs) are multipotent progenitors that can be found in many connective tissues, including fat, bone, cartilage, and muscle. We report here a method to reproducibly differentiate human embryonic stem cells (hESCs) into MSCs that does not require the use of any feeder layer. The cells obtained with this procedure are morphologically similar to bone marrow MSCs, are contact-inhibited, can be grown in culture for about 20 to 25 passages, have an immunophenotype similar to bone marrow MSCs (negative for CD34 and CD45 and positive for CD13, CD44, CD71, CD73, CD105, CD166, human leukocyte antigen [HLA]-ABC, and stage-specific embryonic antigen [SSEA]-4), can differentiate into osteocytes and adipocytes, and can be used as feeder cells to support the growth of undifferentiated hESCs. The ability to produce MSCs from hESCs should prove useful to produce large amounts of genetically identical and genetically modifiable MSCs that can be used to study the biology of MSCs and for therapeutic applications.

10.1634/stemcells.2005-0648

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Citations (206)

<i>Erratum</i> to: Stem cell factor and erythropoietin-independent production of cultured reticulocytes

Haematologica (2020)

Emmanuel Olivier Shouping Zhang Zi Yan Eric E. Bouhassira

10.3324/haematol.2024.286256

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Citations (0)

Fetuin-B, a second member of the fetuin family in mammals

Biochemical Journal (2000)

Emmanuel Olivier Emmanuelle Soury Philippe Ruminy Annie HUSSON Françoise Parmentier