PIM2, an enzyme necessary for the differentiation of B cells and a promising target to treat multiple myeloma

Biologists from Rennes, with the help of colleagues from Toulouse, Montpellier et Limoges, have decrypted the role of the protein kinase PIM2 in the normal differentiation of B cells into plasma cells and in the inhibition of the triggering of their death (apoptosis). These authors show that therapeutic inhibition of PIM2 could improve the efficacy of treatments against multiple myeloma. Paper featured on the cover of Blood - the flagship journal of the American Society of Hematology (14 April 2022).
Immunofluorescently labelled bone biopsy of multiple myeloma. PIM2, in green, is intensely expressed by tumour plasma cells in red. Image: M. Haas et al.

Background: the differentiation of B cells

Along their maturation pathway, B cells (immune cells found in the bloodstream) experience a series of changes. If exposed to an antigen (derived from a virus, a bacterium, toxins, etc.), some of B-cells can differentiate into memory cells and plasma cells, so-called effector cells, that are capable of producing antibodies to fight foreign substances.

Role of the protein kinase PIM2

By studying in vitro the differentiation of human B cells, taken from healthy subjects, researchers from MOBIDIC laboratory in Rennes (Université de Rennes 1/Inserm) have discovered a mechanism involving the protein kinase PIM2 (Proviral Integrations of Moloney Virus 2). The latter directly affects the transformation of a B cell into an effector cell by promoting cell division, an early stage of the differentiation.

PIM2 also acts at the level of mitochondria, the tiny structures found in cells considered to be their “power plants”, blocking the signal that would trigger cell death by apoptosis: this is the most common outcome for B cells, due to poor preparation for differentiation.

By studying in vitro the differentiation of human B cells, taken from healthy subjects, researchers from MOBIDIC laboratory in Rennes (Université de Rennes 1/Inserm) have discovered a mechanism involving the protein kinase PIM2 (Proviral Integrations of Moloney Virus 2). The latter directly affects the transformation of a B cell into an effector cell by promoting cell division, an early stage of the differentiation.
PIM2 also acts at the level of mitochondria, the tiny structures found in cells considered to be their “power plants”, blocking the signal that would trigger cell death by apoptosis: this is the most common outcome for B cells, due to poor preparation for differentiation.

Multiple myeloma and PIM2 targeting

In multiple myeloma, a bone marrow cancer diagnosed in 4 000 new patients per year in France and in nearly 180 000 patients worldwide, there is a pathological proliferation of malignant plasma cells that escape death by apoptosis and strongly express PIM2 (marked in green at the figure above). The survival of these tumour cells depends on anti-apoptotic proteins, primarily PIM2. It seems that the intensity of PIM2 expression in the tumour cells is linked to the clinical severity of the disease.

It is therefore interesting to develop medications capable of targeting PIM2, which would promote the apoptosis of plasma cells involved in myeloma. In addition, the researchers were able to show a possible synergy between this approach and the effects of existing treatments capable of acting on another anti-apoptotic protein called MCL1 (Myeloid Cell Leukemia-1).

Antisense RNAs for specific targeting of PIM2

The current difficulty is to specifically target PIM2. There are other kinases of this type, but also, more generally, many kinases in a cell. The difficulty in targeting these kinases specifically explains the significant toxicity of certain molecules developed by the pharmaceutical industry in recent years.  
In this context, the paper authors explore the use of so-called “antisense” RNAs, molecules that specifically attach themselves to the manufacturing code of PIM2, preventing its reading and therefore the synthesis of the protein kinase by the tumour cells.

Future perspectives: patent registration and therapeutic opportunities

Considering these highly promising findings, the researchers registered a patent in partnership with Inserm Transfert. They have also received financial support from the Université de Rennes 1 to study a mouse model to evaluate the effectiveness in vivo of antisense RNA. In addition, collaborations have been established to rapidly exploit the opportunities.

Within the MOBIDIC joint research unit (Université de Rennes 1/Inserm), the B_DEVIL team is fully mobilised to continue the discovery of PIM kinases in biology, and normal and tumour differentiation of B cells.

References and collaboration

Pivotal role of PIM2 kinase in plasmablast generation and plasma cell survival, opening new treatment options in myeloma (open access by June 3, 2022)
Marion Haas,Gersende Caron, Fabrice Chatonnet,Stephane Manenti, Elina Alaterre, Julie Devin, Celine Delaloy, Giulia Bertolin, Roselyne Viel, Amandine Pignarre, Francisco Llamas-Gutierrez, Anne Marchalot, Olivier Decaux, Karin Tarte, Laurent Delpy, Jerôme Moreaux, and Thierry Fest
Blood, 14 April 2022 | VOLUME 139, NUMBER 15: 2316-2337 | doi: https://doi.org/10.1182/blood.2021014011

In Toulouse, the researchers helped to understand PIM2 in normal differentiation; in Montpellier, they provided the authors with myeloma cell lines and data for patients; in Limoges, they helped them with the design of the antisense RNA. All the work was carried out in Rennes, primarily by Marion Haas, a PhD student at the Université de Rennes 1 and a pharmacist biologist.

Institutions, research units and services involved:

1.    Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, Unité Mixte de Recherche (UMR)_S1236, Rennes, France
2.    Laboratoire d'hématologie et immunologie, Pôle de Biologie, Centre Hospitalier Universitaire, Rennes, France
3.    Université de Toulouse, Centre National de la Recherche Scientifique (CNRS) Equipe de Recherche Labellisée (ERL) 5294, INSERM U1037, Centre de Lutte Contre le Cancer, Toulouse, France
4.    Institut de Génétique Humaine, UMR 9002 CNRS-UM, Pôle de biologie, Centre Hospitalier Universitaire, Montpellier, France
5.    Université de Rennes, CNRS, Institut de Génétique & Développement de Rennes, UMR 6290, Rennes, France
6.    Plateforme H2P2, Rennes, France
7.    Laboratoire d'Anatomie Pathologique, Pôle de Biologie, Centre Hospitalier Universitaire, Rennes, France
8.    Université de Limoges, UMR CNRS 7276, INSERM U1262, Limoges, France
9.    Service d'hématologie clinique, Centre Hospitalier Universitaire, Rennes, France