Ikaros increases normal apoptosis in adult erythroid cells

Abstract

Ikaros is a critical transcriptional regulator of hematopoietic cell differentiation. In addition to its effects on the lymphoid system and hematopoietic stem-cell compartment, we have previously shown that Ikaros is also required for normal erythroid development. In this report, we compare Ikaros-dependent gene expression in erythroid cells of mice lacking the Ikaros protein with that of normal mice in purified adult bone-marrow erythroid cells (BMRC). Gene expression, measured by Affymetrix microarray analysis, indicates that in the BMRC of Ikaros-null mice, there is significant up-regulation of SMADs 6 and 7, serine protease inhibitor 3, and immediate-early protein 3 (IER3), all proteins that play a modulating role in apoptosis. We investigate the role of Ikaros in oxidative stress-induced apoptosis using Annexin-V staining and FACS analysis. We find a decrease in apoptosis in the BMRC of Ikaros-null mice compared to normal mice. This effect is also seen in nonerythroid cells but is stronger in BMRC. We conclude that normal Ikaros function increases normal apoptosis in erythroid cells. The data also suggest that Ikaros plays a role in apoptosis-mediated events in other normal hematopoietic cell lineages. Am.

GATA-1 Utilizes Ikaros and Polycomb Repressive Complex 2 To Suppress Hes1 and To Promote Erythropoiesis

“…GATA-1 and Ikaros were both reported to influence EryC homeostasis (17,38,42,45,51,55,56,59,62). GATA-1 regulates a number of genes in EryC; however, to date only a few Ikaros-regulated genes have been identified in these cells (3,5,45).…”

“…GATA-1 and Ikaros were both reported to influence EryC homeostasis (17,38,42,45,51,55,56,59,62). GATA-1 regulates a number of genes in EryC; however, to date only a few Ikaros-regulated genes have been identified in these cells (3,5,45). While an expression array revealed that the absence of Ikaros causes variable expression of different genes controlling apoptosis in EryC (45), the precise effect of Ikaros on erythroid gene regulation has been studied mainly at the ␤-globin locus (3,5,7).…”

“…The absence of Ikaros, such as in Ikaros-null (Ik null ) mice, results in a severe defect in B-and T-lymphopoiesis and reduces hematopoietic stem cell activity (38,58). However, many questions as to why adult Ik null mice also exhibit anemia remain unanswered (38,45).…”

Ikaros expression sensitizes leukemic cells to the chemotherapeutic drug doxorubicin

“…Besides their roles in the differentiation of specific lineages of hematopoietic cells, the Ikaros family members were recently reported to be involved in the apoptosis of hematopoietic cells (19). For example, bone marrow erythroid cells derived from Ikaros-null mice are more resistant to apoptosis than those from wild-type mice (19).…”

“…Besides their roles in the differentiation of specific lineages of hematopoietic cells, the Ikaros family members were recently reported to be involved in the apoptosis of hematopoietic cells (19). For example, bone marrow erythroid cells derived from Ikaros-null mice are more resistant to apoptosis than those from wild-type mice (19). Aiolos, another member of the Ikaros family, has also been reported to control T-cell death by upregulating the expression of Bcl-2 (20), which is consistent with the present observation that IK1 regulates the expression of the apoptosis-associated protein caspase-9.…”