Role of Ikaros in T-cell acute lymphoblastic leukemia

Table 1 Mutations of Ikaros in murine T-cell lymphomas

Study	Model	Alteration studied	Type and frequency of Ikaros anomalies
Matsumoto et al[40], 1998	γ-irradiation (Balb/c-MSM F1 hybrids)	Genome-wide LOH mapping (microsatellites)	Allelic loss in proximal chromosome 11 region: 40% (8/20)
Okano et al[41], 1999	γ-irradiation (Balb/c-MSM F1 hybrids)	LOH (polymorphic restriction site)	Allelic loss: 54% (99/182)
		Mutation analysis (SSCP and cDNA sequencing)	Homozygous deletions: 8/1081
			Missense point mutations in DBD: 5/1081
			Frame-shift or stop codon point mutations: 6/1081
Shimada et al[42], 2000	X-ray-induced thymic lymphomas	LOH (microsatellite mapping)	Distal region of chromosome 11 containing the Ikzf1 gene identified as a common deleted region in 50% of cases
Kakinuma et al[43], 2002	X-ray-induced thymic lymphomas	LOH RNA expression (RT-PCR) Protein expression (Western blotting) Point mutations	LOH for Ikzf1 in 20/37 tumors
			No or dn transcripts in 9/37 tumors (correlated with absence of Ikaros proteins or presence of dn Ikaros proteins)
			Point mutations in 9/37 tumors (mostly zinc finger point mutations)2
Karlsson et al[44], 2002	Mutagen-induced thymic lymphoma	Point mutation analysis (SSCA and sequencing) Deletions (Southern) Allelic loss (microsatellite)	8 DBD point mutations (8/104)
			3 frame-shift mutations (3/104)
			27% allelic loss (12/40)
			3 homozygous deletions (3/68)
Beverly et al[15], 2003	Notch1-IC transgenic mice	cooperating retroviral insertions	40% (synthesis of dn proteins)
López-Nieva et al[18], 2004	γ-irradiation (C57Bl6-Balb/c hybrids)	LOH (polymorphic restriction site)	42% (32/75) of LOH (1 homozygous deletion)
		Point mutations (SSCP and sequencing)	1 missense mutation in DBD
Kakinuma et al[45], 2005	Mutagen-induced thymic lymphoma	LOH	LOH: 2/27
		Point mutations	Point mutations: 5/27 (all in zn finger regions)
Kang et al[46], 2006	γ-irradiation (C57BL/6)	CGH-array (BAC)	Focal loss of chromosome 11: 20% (2/10)
Kakinuma et al[47], 2007	Mlh1-deficient mice (20 spontaneous or radiation-induced lymphomas)	Point mutation analysis	Frame-shift point mutations: 85% (17/20)
		Western blotting	Lack of Ikaros protein: 75% (15/20)
Ohi et al[48], 2007	γ-irradiation (Balb/c-MSM F1 hybrids)	LOH (polymorphic restriction site)	43% (15/35)
Yoshida et al[49], 2007	X-irradiation (C57Bl6-C3H F1 hybrids)	Karyotype	Interstitial deletion of the proximal chromosome 11: 27% (7/15)
Uren et al[19], 2008	p19ARF- and p53- deficient mice	Common retroviral insertions (CIS)	33/5103 (mostly in p19ARF-deficient mice; strong association with Notch1 activation
Dail et al[20], 2010	KrasG12D-induced thymic lymphomas	Retroviral insertional mutagenesis	30% (9/30) insertions into Ikaros gene leading to synthesis of dn proteins

¹The 108 tested samples include the 99 with loss of heterozygosity (LOH);

²The tumors with point mutations are distinct from those exhibiting abnormal transcripts;

³11 out of the 33 tumors had more than one hit in the Ikaros gene. CGH: Comparative genomic hybridization; SSCP: Single strand conformation polymorphism; SSCA: Single strand conformation analysis; dn: Dominant-negative; RT-PCR: Reverse transcription polymerase chain reaction.

Table 2 Studies of Ikaros status in human T-cell acute lymphoblastic leukemia

Study	No. of patients	Methods used	Cases with Ikaros abnormalities
Sun et al[30]	18 (pediatric)	WB, EMSA, IF, RT-PCR	18/18
Nakase et al[50]	5 (adult)	RT-PCR	0/5
Ruiz et al[51]	9 (pediatric)	RT-PCR, WB	0/9
Maser et al[52]	24 (16 cell lines and 8 primary leukemias)	CGH-array	2/24
Kuiper et al[53]	7 (unknown origin)	CGH-array	0/7
Meleshko et al[54]	14 (pediatric)	RT-PCR	1/14 (expression of dn Ik6 isoform)
Mullighan et al[6]	50 (unknown origin)	CGH-array	2/50
Marçais et al[31]	25 (adult, pediatric)	CGH-array, RT-PCR, WB, IF, cDNA sequencing	1/25

WB: Western blotting; EMSA: Electrophoretic mobility shift assay; IF: Immunofluorescence; RT-PCR: Reverse transcription polymerase chain reaction.