Inserm U1287, Gustave Roussy, Villejuif, France ; Université Paris-Saclay, faculté de médecine, Le Kremlin-Bicêtre, France
Conflits d’interet : L’équipe a reçu un soutien financier des laboratoires Servier (qui a généré un inhibiteur de MCL1 mentionné dans cette revue) et de la Fondation Amgen pour la science.
Chronic myelomonocytic leukemia (CMML) is classified by the World Health Organization as a myelodysplastic/ myeloproliferative neoplasm (MDS/MPN). Observed mostly in ageing people, this chronic myeloid malignancy is characterized by the expansion of CD14+, CD16-classical monocytes expressing pro-inflammatory genes. In most cases, granulocytes also expand, some of them being endowed with immunosuppressive properties. The disease is driven by the accumulation, in the stem cell compartment, of somatic variants in epigenetic, splicing and signaling genes, and by epigenetic reprogramming. As a consequence of abnormal DNA methylation, the repartition of circulating monocyte subsets is altered. An increase in the fraction of classical CD14+CD16-monocytes (>94%), or a decrease in the fraction of non-classical CD14low,CD16+,Slan+ monocytes (1.7%), among total circulating monocytes are diagnostic features. In some patients, mature cells of the leukemic clone include plasmacytoid dendritic cells forming islands in the bone marrow, or mastocytes that infiltrate the skin or expand within other tissues. Cytokines and chemokines released by leukemic cells contribute to create an inflammatory climate that either promote the expansion of the leukemic clone or reduce the growth of wild-type cells. The suspected role of other components of the bone marrow niche in driving CMML emergence and progression remains poorly understood. Clinical expression of the disease is diverse, with time-dependent accumulation of symptoms eventually leading to physical exhaustion and patient death as a consequence of cytopenias, acute leukemia transformation and comorbidities. Fifty years after its identification, CMML remains one of the most severe chronic myeloid malignancies in which allogeneic stem cell transplantation is the only disease-modifying therapy. The proliferative component of the disease deserves specific therapeutic approaches, distinct from those explored in myelodysplastic neoplasms. The present review emphasizes CMML specificities and discusses how this disease could benefit from dedicated therapies.