Credit: Aaron Logan
Two papers published in Nature Immunology have shed new light on the role of Ikaros in B-cell acute lymphoblastic leukemia (B-ALL).
In one paper, researchers describe experiments in mice that show a defect in Ikaros function can disrupt lymphopoiesis and prevent the development of mature B cells.
The cells stay in an aberrant state, which closely resembles that of cells in human B-ALL.
The other paper provides insight into how pre-B cells transition from a proliferative phase to a differentiation phase.
Investigators found that this process, which is vulnerable to leukemic transformation, is dependent upon Ikaros.
Ikaros defect in mice mimics human B-ALL
In the first sudy, researchers showed that loss of Ikaros function in mice creates an environment that mimics human B-ALL.
“We already know several transcription factors that play a central role in B-cell differentiation,” said study author Meinrad Busslinger, PhD, of the Research Institute of Molecular Pathology in Vienna, Austria.
“Pax5, for example, represents a critical factor which activates the B-cell-specific program in precursor cells and simultaneously suppresses alternative cell fates. For Ikaros, we did not know, until now, what this factor is doing during early B-cell development.”
To find out, he and his colleagues analyzed mice that lacked Ikaros from an early stage of B-cell development on. They found that Ikaros deficiency arrested B-cell development due to a defect in pre-BCR signaling.
The cells remained in an aberrant, pro-B-cell stage and were prevented from further differentiation. They also showed increased cell adhesion and reduced migration compared to normal cells.
The researchers noted that loss of Ikaros function has previously been associated with the development of B-ALL. As in mice with a mutated Ikaros gene, B cells from B-ALL patients are arrested at an early checkpoint of B-cell development.
Loss of Ikaros in pre-B cells
With the second study, investigators provided new insight into pre-B-cell differentiation. They described the cells’ transition from a stroma-adherent proliferative phase to a nonadherent differentiation phase.
The stroma-adherent pre-B cells were highly proliferative and had limited self-renewing potential. But when they transitioned to the nonadherent phase, they exited the cell cycle, lost their capacity for self-renewal, and acquired the expression of genes encoding molecules that support B-cell maturation.
And this transition was dependent upon Ikaros.
“Loss of function in the transcription factor Ikaros appears to create a differentiation block that drives the pre-B cells into an adhesive state, promotes self-renewal, and primes them for malignant potential,” said study author Richard Van Etten, MD, PhD, of the University of California, Irvine.
Furthermore, the survival and proliferation of the Ikaros-deficient pre-B cells appeared to be dependent on cooperation between signaling via integrins and signaling via receptors for growth factors.
The researchers said this discovery points to a new avenue for treating B-ALLs resulting from Ikaros mutations.
