Ikaros has an essential role in the differentiation of B lymphocytes
IL-7 withdrawal induces differentiation of wild-type pro-B cells (right), but not of cells that do not express Ikaros (left). Differentiation is visualized by the expression of the immunoglobulin heavy (μ) and light (K/λ) chains, analyzed by flow cytometry.
J Exp Med Dec. 16, 2013
Dec. 16, 2013
B-cell acute lymphoblastic leukemia (B-ALL) are cancers affecting B lymphocytes, major cells of the immune system. In approximately 30% of cases, these are highly aggressive leukemias, associated with mutations of a gene encoding the transcription factor Ikaros. The team of Philippe Kastner and Susan Chan has highlighted the crucial role of this factor in the differentiation of B lymphocytes. This discovery is a major breakthrough in the understanding of B-cell development and opens the way to a better understanding of the mechanisms of leukemogenesis of B-ALL. These results were published on December 16th in the Journal of Experimental Medicine.
Leukemia and cancer
Leukaemias are cancers that affect the bone marrow cells. Philippe Kastner and Susan Chan are particularly interested in B-cell acute lymphoblastic leukemia (B-ALL) that specifically affect B-cells. In 30% of cases, B-ALL exhibit mutations of the IKZF1 gene, which encodes the transcription factor Ikaros. These leukemias are associated with poor prognosis. The mechanisms underlying the tumor suppressor role of Ikaros remains unknown.
B cell differentiation
B Lymphocytes are important cells of the immune system which produce antibodies. These cells originate from hematopoietic stem cells in the bone marrow and go through several stages of maturation (pre-proB, proB, large preB, small preB, etc.) before being functional. Interleukin 7 (IL-7) is an essential molecule for the early differentiation of B lymphocytes and its action has to be inhibited during the later stages.
New model for the study of Ikaros
Several clues had previously suggested a possible role for Ikaros in the differentiation of B lymphocytes. However, its precise role remained unknown, as mice deficient for this factor lack all B lineage cells. After several years of efforts, the researchers have been able to develop a new mouse model, in which the Ikaros function is specifically inhibited from the proB stage. They have found that Ikaros is absolutely required for the transition between the "large preB" to the "small preB" stages. At this stage, the cells must also escape the action of IL-7 to differentiate. The team has shown that Ikaros inhibits the gene expression program that is dependent on IL7.
This finding identifies a new key player in the maturation of B lymphocytes and opens the way to the understanding of the tumor suppressor role of Ikaros in certain leukemias.