gene encodes a zinc finger, DNA-binding protein that acts as regulator of gene transcription and chromatin remodeling[1
]. Studies of Ikaros mutant mice have established Ikaros as a master regulator of hematopoiesis[1
]. Partial arrest or defects in normal hematopoiesis often lead to aberrant cellular proliferation and leukemia/lymphoma, therefore, it is not surprising that Ikaros knockout mice that lack one copy of Ikaros develop T cell leukemia[2
]. The remarkable observation is that these mice developed T cell leukemia with 100% penetrance, and in each case, the leukemic clones arose from cells that had lost the single wild-type Ikaros
]. This suggests an essential role for Ikaros as a tumor suppressor in T cell differentiation. In humans, defects in the Ikaros
gene (90% of observed defects involved deletions of one allele, while the remainder involved nonsense or functionally inactivating mutations of a single allele) can result in the production of dominant negative (DN) Ikaros isoforms that act to suppress the function of full-length Ikaros. Ikaros
defects have been associated with the development of a variety of hematopoietic malignancies. These include childhood acute lymphoblastic leukemia (ALL)[3
] infant T-cell ALL[5
], adult B cell ALL[6
], myelodysplastic syndrome[7
], acute myeloid leukemia[8
], and adult and juvenile chronic myeloid leukemia[9
defects leading to a loss of Ikaros activity have been detected in 30% of pediatric B-cell ALL, in > 80% of BCR-ABL1 ALL, and approximately 5% of T-cell ALL[10
]. In addition, defective Ikaros
has been identified as a poor prognostic marker for childhood ALL[4
]. A noteworthy observation is that, in almost all primary human leukemia cells in which an Ikaros
defect is observed, one wild-type Ikaros copy is retained. These data not only show a strong association between the loss of Ikaros function and the development of human leukemia, but also suggest that even a moderate alteration of Ikaros function (e.g. haploinsufficiency) is sufficient to promote malignant transformation. The aberrant expression of small DN Ikaros isoforms has also been associated with the development of human pituitary adenoma[15
]. The current hypothesis is that small Ikaros isoforms act as DN mutants in human cells and their overexpression promotes malignant transformation, while the full-length Ikaros acts as a tumor suppressor.
Several crucial questions remain unanswered. (1) Is the loss of Ikaros activity an essential step in the malignant transformation of hematopoietic cells? (2) How is the function of Ikaros regulated in normal and leukemia cells? (3) Can alterations in the regulation of Ikaros function contribute to the development of leukemia?
A partial answer to the first question came when the T leukemia cells derived from Ikaros-deficient mice were transduced with retrovirus to express wild-type Ikaros. The introduction of wild-type Ikaros at physiological levels led to cessation of growth, induction of T-cell differentiation, and cell cycle arrest in Ikaros-deficient T-leukemia cells[16
]. These results suggest that the presence of functional wild-type Ikaros, at physiological levels, is sufficient to arrest the aberrant proliferation of malignant cells. This experiment involved a single leukemia cell line that completely lacked Ikaros expression, therefore, this does not fully answer the question of whether the loss of Ikaros function is an essential step in leukemogenesis, although it does underscore the importance of functional Ikaros in tumor suppression. To address these issues regarding the importance of the regulation of Ikaros activity in the development of leukemia, the first step will be to identify the mechanisms that regulate Ikaros activity in normal and malignant hematopoiesis, and to dissect their role in regulating the function of Ikaros.