Cancer Research Infection and Cancer: Biology, Therapeutics, and Prevention Joint Metastasis Research Society-AACR Conference on Metastasis
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nakase, K.
Right arrow Articles by Harada, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nakase, K.
Right arrow Articles by Harada, M.
[Cancer Research 60, 4062-4065, August 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Dominant Negative Isoform of the Ikaros Gene in Patients with Adult B-Cell Acute Lymphoblastic Leukemia

Koichi Nakase, Fumihiko Ishimaru1, Nicole Avitahl, Hiromichi Dansako, Keitaro Matsuo, Keiko Fujii, Nobuo Sezaki, Hiroyuki Nakayama, Tomofumi Yano, Shunnichi Fukuda, Kenji Imajoh, Makoto Takeuchi, Akira Miyata, Masamichi Hara, Masaki Yasukawa, Isao Takahashi, Hirokuni Taguchi, Kosei Matsue, Shinji Nakao, Yoshiyuki Niho, Katsuto Takenaka, Katsuji Shinagawa, Kazuma Ikeda, Kenji Niiya and Mine Harada

Department of Medicine, University of Okayama [K. Na., F. I., H. D., K. Matsuo, K. F., N. S., H. N., K. T., K. S., K. Ik., K. Ni., M. Harad.], Okayama Rousai Hospital [T. Y.], National Okayama Hospital [S. F.], Okayama Municipal Hospital [K. Im.], and National Sanatorium Minami Okayama Hospital [M. T.], Okayama 700-8558, Japan; Chugoku Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuyama 721-0975, Japan [A. M.]; Ehime Prefectural Central Hospital [M. Hara], Department of Medicine, University of Ehime [M. Y.], Ehime 791-0295, Japan; Kochi Municipal Central Hospital [I. T.], Department of Medicine, Kochi Medical School [H. T.], Kochi 783-8505, Japan; Kameda General Hospital, Kamogawa 296-0041, Japan [K. Matsue]; Department of Medicine, University of Kanazawa, Kanazawa 920-8641, Japan [S. N.]; Department of Medicine, University of Kyushu, Fukuoka 812-8582, Japan [Y. N.]; and Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129 [N. A.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Gene targeting studies in mice have shown that the transcription factor Ikaros plays an essential role in lymphoid development and as a tumor suppressor in T cells, whereas the related gene Aiolos functions as a tumor suppressor in B cells. We analyzed the expression levels of the Ikaros gene family, Ikaros and Aiolos, in human bone marrow samples from patients with adult acute lymphoblastic leukemia [ALL (n = 46; B-cell ALL = 41; T-cell ALL = 5)]. Overexpression of the dominant negative isoform of Ikaros gene Ik-6 was observed in 14 of 41 B-cell ALL patients by reverse transcription-PCR, and the results were confirmed by sequencing analysis and immunoblotting. None of the other dominant negative isoforms of the Ikaros gene were detected by reverse transcription-PCR analysis. Southern blotting analysis with PstI digestion revealed that those patients with the dominant negative isoform Ik-6 might have small mutations in the Ikaros locus. We did not detect any overexpression of dominant negative isoforms of Aiolos in adult ALL patients. These results suggest that Ikaros plays a key role in human B-cell malignancies through the dominant negative isoform Ik-6.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The Ikaros gene has been shown in the murine model to be essential for the development of B lymphocytes and to function as a tumor suppressor in T lymphocytes (1, 2, 3) . By means of alternate splicing, Ikaros encodes several zinc finger proteins that differ in their content of zinc fingers that mediate DNA binding (4) . Thus, the various isoforms differ in their abilities to bind stably to a consensus Ikaros DNA-binding site. Ikaros proteins multimerize via zinc fingers located in the COOH termini of the proteins; thus, isoforms that lack a DNA-binding domain (Ik-6, Ik-7, and Ik-8) can interact with proteins that have a DNA-binding domain (Ik-1, Ik-2, and Ik-3) and interfere in a dominant negative fashion with their ability to bind DNA (5) . Expression of high levels of dominant negative isoforms can reduce Ikaros activity by titrating out the DNA-binding activities of the predominant isoforms Ik-1, Ik-2, and Ik-3. In addition, dominant negative Ikaros isoforms can interact with the homologous proteins Aiolos (6, 7, 8) and Helios (9 , 10) to reduce their DNA-binding activities. In mice, T-cell malignancies result from mutations that reduce Ikaros activity either by ablating expression altogether via a null mutation (3) or by causing overexpression of dominant negative isoforms that titrate out activity of isoforms Ik-1, Ik-2, and Ik-3 (2) . The fact that Ikaros functions as a tumor suppressor in mice prompted us (11) and others (12, 13, 14) to ask whether alterations in Ikaros activity might be similarly important in human hematological malignancies. In a previous report (11) , we correlated the development of blast crisis in patients with chronic myelogenous leukemia with a reduction in Ikaros activity. In several bone marrow samples from patients who were in blast crisis, Ikaros expression was severely reduced at the RNA level, whereas in other samples, activity was reduced through the overexpression of dominant negative Ik-6. Sun et al. (12, 13, 14) reported overexpression of the dominant negative isoforms Ik-7 and Ik-8 in leukemic cells in several cases of infant and T-ALL.2 Thus, the reports of Sun et al. (13 , 14) correlate reductions in Ikaros activity (i.e., overexpression of dominant negative Ikaros isoforms) with T-cell malignancies, as observed in the murine model. We have shown that mutations that affect Ikaros activity can also be involved in non-T-cell malignancies such as blast crisis of chronic myelogenous leukemia (11) . We have extended these studies to demonstrate that mutations that cause overexpression of dominant negative Ikaros isoforms can be involved in B-cell malignancies in humans. Here we show that in 14 of 41 patients with adult B-ALL, Ikaros activity was reduced through overexpression of the dominant negative isoform Ik-6. These results suggest that mutations that reduce Ikaros activity can contribute to the development of B-cell malignancies in humans.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
RT-PCR Analysis.
Bone marrow aspirates were obtained from patients after obtaining informed consent. Characteristics of adult B-ALL patients are shown in Table 1Citation . All patients had a negative myeloperoxidase test. RT-PCR analysis was performed as described previously (11) . The sequences of the primers used are as follows: (a) Ikaros sense, 5'-CACATAACCTGAGGACCATG-3'; (b) Ikaros antisense, 5'-AGGGCTTTAGCTCATGTGGA-3' (4) ; (c) Aiolos sense, 5'-CCCGGCAGCGACATGGAAGA-3'; and (d) Aiolos antisense, 5'-CCAGATATTCACTTCAGCAG-3' (8) . Bone marrow samples from five T-ALL, six ALL (L3), and five adult T-cell leukemia patients were also examined. Major and minor BCR/ABL fusion transcripts were analyzed by RT-PCR (Table 1)Citation .


View this table:
[in this window]
[in a new window]
  		Table 1 Patient characteristics of adult B-ALL

 
Sequencing Analysis.
The PCR products were subcloned into the pCR2.1-TOPO vector using the TOPO TA Cloning Kit (Invitrogen, San Diego, CA). The sequencing analysis was performed by using the ABI 373 DNA Sequencer (Perkin-Elmer, Foster City, CA).

Immunoblotting.
Extraction of whole cell lysates and immunoblotting were performed as described previously (15) . The membranes were incubated with anti-Ikaros antibody or anti-Sp1 antibody (Santa Cruz Biotechnology, Santa Cruz, CA).

Southern Blotting.
Southern blotting was performed as described previously (16) . The human Ikaros cDNA used as a hybridization probe was labeled with [{alpha}-32P]dCTP using the High Prime DNA labeling kit (Boehringer Mannheim, Indianapolis, IN).


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
The expression levels of the Ikaros family genes, Ikaros (4) and Aiolos (8) , in bone marrow samples from adult ALL patients (n = 46; B-ALL = 41; T-ALL = 5) were analyzed by performing RT-PCR (Fig. 1Citation and data not shown). The expression of the largest isoforms (Ik-1, Ik-2, and Ik-3) of the Ikaros gene was predominant, as described previously (4) . However, in 14 of 41 patients with adult B-ALL, the dominant negative isoform Ik-6 was the predominant isoform expressed (Fig. 1Citation and Table 1Citation ; patients 1–4, 15–17, and 35–41). These results were confirmed by sequencing analysis (data not shown). In contrast to the previous reports (12, 13, 14) , none of the other dominant negative isoforms (Ik-7 and Ik-8) were found in adult ALL patients, although Ik-4 is normally expressed at a low level. There was a trend that expression of the dominant negative isoform Ik-6 was correlated with expression of BCR/ABL fusion transcripts (Table 1)Citation , although it was not statistically significant ({chi}2 test, P = 0.18). We found no dominant negative isoforms of the Ikaros gene in bone marrow samples from five T-ALL, six ALL (L3), and five adult T-cell leukemia patients (data not shown).



View larger version (50K):
[in this window]
[in a new window]
  		Fig. 1. RT-PCR analysis of the Ikaros isoforms and Aiolos in bone marrow samples. The PCR products of Ikaros and Aiolos from human bone marrow samples were analyzed on a 1% agarose gel with a 100-bp ladder molecular marker (Lane M). Lanes 1–41 show the PCR products of the patients with B-ALL (Table 1Citation , patients 1–41, respectively). The PCR products of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) are also shown as a control.

 
The Ikaros family member gene Aiolos was shown in mice to be important for regulated proliferation of B cells (7) . We therefore determined whether altered levels of Aiolos expression correlated with incidence of B-ALL. Unlike Ikaros, which has several splice forms, Aiolos has only one splice form. In the patient samples examined, we detected only the reported isoform of Aiolos; no dominant negative isoforms were observed. However, Aiolos expression appeared to be decreased in several patients (Fig. 1Citation ; patients 1, 14, 15, 25, 32, 35, 37, and 38).

The overexpression of the dominant negative Ik-6 protein in bone marrow cells from adult ALL patients was confirmed by immunoblotting of whole cell lysates using an anti-Ikaros antibody. Whole cell lysate from the Jurkat cell line showed Ik-1, Ik-2, and Ik-3 as the major isoforms present, as reported previously (4) . However, in whole cell lysates from patients who demonstrated overexpression of the dominant negative isoform Ik-6 (Fig. 1Citation , patients 1, 35, and 37), significant amounts of Ik-6 protein were detected (Fig. 2Citation ). These data confirm the results of the RT-PCR analysis (Fig. 1Citation ).



View larger version (10K):
[in this window]
[in a new window]
  		Fig. 2. Immunoblotting study of whole cell lysates from bone marrow samples. Whole cell lysates from patients with the dominant negative isoform Ik-6 (Table 1Citation , patients 1, 35, and 37) were analyzed using an anti-Ikaros antibody as the primary antibody. The positions of molecular weight standards and Ikaros isoforms are indicated. The lysates were also analyzed with an anti-Sp1 antibody as a control.

 
To determine whether a genetic lesion could be correlated with overexpression of the dominant negative isoform Ik-6, Southern blot analysis was performed using human Ikaros cDNA as a probe. PstI digests of genomic DNA revealed differences in the restriction fragments between normal volunteers (n = 10) and patients with the dominant negative isoform Ik-6 [n = 4 (Fig. 3Citation )]. A novel band indicated by an arrow was observed in DNA from the BV-173 cell line and in patients who showed overexpression of the dominant negative isoform Ik-6 (Fig. 1Citation , patients 2, 15, 35, and 37). No gross abnormalities could be detected with BamHI and EcoRI digestion (data not shown).



View larger version (32K):
[in this window]
[in a new window]
  		Fig. 3. Southern blotting analysis of the genomic DNA from bone marrow samples. Genomic DNA from normal volunteers, the Jurkat and BV-173 cell lines, and patients with the dominant negative isoform Ik-6 (Table 1Citation , patients 2, 15, 35, and 37) was analyzed with the human Ikaros cDNA probe by PstI digestion. The positions of {lambda}/HindIII markers are shown. The novel bands are indicated by an arrow.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
In the present analysis, RT-PCR was used to determine the expression levels of the Ikaros family genes, Ikaros and Aiolos, in bone marrow samples from adult ALL patients (n = 46; B-ALL = 41; T-ALL = 5). In 14 of 41 cases of adult B-ALL patients, Ikaros activity was reduced by overexpression of the dominant negative isoform Ik-6. Due to the limited amounts of bone marrow samples, immunoblotting analyses could only be performed on the samples from patients 1, 35, and 37 (Table 1)Citation . These experiments demonstrated that the dominant negative Ik-6 protein was stably expressed at high levels in those patients. PstI digests of genomic DNA revealed differences in the restriction fragments between normal volunteers (n = 10) and patients with the dominant negative isoform Ik-6 (n = 4). No gross abnormalities could be detected in those patients with BamHI and EcoRI digestion, suggesting that a mutation in the Ikaros locus may alter gene splicing, resulting in aberrantly high levels of Ik-6. It is interesting that we detect the same novel restriction fragments at a relatively high frequency, and we are currently determining which region of the locus is affected.

Because the related gene Aiolos was shown in mice to be a tumor suppressor gene in B cells (7) , we expected that Aiolos activity might also be reduced in cases of B-ALL. Although Aiolos expression appeared to be decreased in several patient samples, it is not clear that this expression was aberrant. In the mouse, Aiolos is normally expressed at very low levels in pro-B cells and becomes greatly up-regulated at the pre-B-cell stage (6) . Unfortunately, we did not have enough material to characterize the developmental stage of these leukemias. Therefore, we cannot make any conclusions about the significance of the low expression levels detected in certain patient samples. Nevertheless, it was clear that no dominant negative splice forms of Aiolos were expressed. Moreover, it is likely that even in the leukemic samples that showed normal levels of Aiolos expression, Aiolos activity was reduced through the dominant negative action of Ik-6, which can interact with Aiolos proteins and interfere with their DNA-binding capacity.

Ikaros and Aiolos are present together in large multiprotein complexes that have chromatin remodeling activity and contain proteins such as Mi-2/histone deacetylases or Brg-1/Swi-3/BAF60 (17 , 18) . The function of Ikaros and Aiolos in these complexes may be to recruit chromatin remodeling activity and histone deacetylases to the appropriate gene targets, thus enabling proper gene expression. The overexpression of dominant negative proteins such as Ik-6 may interfere with the ability of these complexes to be properly recruited to target genes. In the case of the M2 form of acute myeloid leukemia, the AML1-ETO fusion protein results in the inappropriate targeting of histone deacetylases (19 , 20) . Thus, aberrant gene expression resulting from inefficient or inappropriate targeting of histone deacetylases may be an important mechanism underlying leukemogenesis.

The results presented here contribute to a growing body of work showing that mutations that alter Ikaros activity correlate with hematological malignancies in humans (11, 12, 13, 14) . Interestingly, unlike the murine model (2 , 3) , in which these malignancies are confined to the T lineage, mutations in the Ikaros locus appear to contribute to malignancy in other hemopoietic lineages. This is likely to be due in some cases to the presence of other genetic lesions, such as BCR/ABL, which may cooperate with a mutation in Ikaros to target a cell that would otherwise not be affected by a mutation in Ikaros alone. Characterizing these potential genetic interactions will be of future interest.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Department of Medicine, University of Okayama, 2-5-1 Shikatacho, Okayama 700-8558, Japan. Phone: 81-86-235-7227; Fax: 81-86-232-8226; E-mail: ishimaru{at}hospital.okayam-u.ac.jp Back

2 The abbreviations used are: T-ALL, T-cell acute lymphoblastic leukemia; ALL, acute lymphoblastic leukemia; B-ALL, B-cell acute lymphoblastic leukemia; RT-PCR, reverse transcription-PCR. Back

Received 3/23/00. Accepted 6/ 8/00.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

  1. Georgopoulos K., Bigby M., Wang J-H., Molnar A., Wu P., Winandy S., Sharpe A. The Ikaros gene is required for the development of all lymphoid lineages. Cell, 79: 143-156, 1994.[Medline]
  2. Winandy S., Wu P., Georgopoulos K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell, 83: 289-299, 1995.[Medline]
  3. Wang J-H., Nichogiannopoulou A., Wu L., Sun L., Sharpe A. H., Bigby M., Georgopoulos K. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity, 5: 537-549, 1996.[Medline]
  4. Molnar A., Wu P., Largespada D. A., Vortkamp A., Scherer S., Copeland N. G., Jenkins N. A., Bruns G., Georgopoulos K. The Ikaros gene encodes a family of lymphocyte-restricted zinc finger DNA binding proteins, highly conserved in human and mouse. J. Immunol., 156: 585-592, 1996.[Abstract]
  5. Sun L., Liu A., Georgopoulos K. Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development. EMBO J., 15: 5358-5369, 1996.[Medline]
  6. Morgan B., Sun L., Avitahl N., Andrikopoulos K., Ikeda T., Gonzales E., Wu P., Neben S., Georgopoulos K. Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J., 16: 2004-2013, 1997.[Medline]
  7. Wang J-H., Avitahl N., Cariappa A., Friedrich C., Ikeda T., Renold A., Andrikopoulos K., Liang L., Pillai S., Morgan B. A., Georgopoulos K. Aiolos regulates B cell activation and maturation to effector state. Immunity, 9: 543-553, 1999.
  8. Hosokawa Y., Maeda Y., Takahashi E., Suzuki M., Seto M. Human Aiolos, an Ikaros-related zinc finger DNA binding protein: cDNA cloning, tissue expression pattern, and chromosomal mapping. Genomics, 61: 326-329, 1999.[Medline]
  9. Hahm K., Cobb B. S., McCarty A. S., Brown K. E., Klug C. A., Lee R., Akashi K., Weissman I. L., Fisher A. G., Smale S. T. Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin. Genes Dev., 12: 782-796, 1998.[Abstract/Free Full Text]
  10. Kelley C. M., Ikeda T., Koipally J., Avitahl N., Wu L., Georgopoulos K., Morgan B. A. Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors. Curr. Biol., 8: 508-515, 1998.[Medline]
  11. Nakayama H., Ishimaru F., Avitahl N., Sezaki N., Fujii N., Nakase K., Ninomiya Y., Harashima A., Minowada J., Tsuchiyama J., Imajoh K., Tsubota T., Fukuda S., Sezaki T., Kojima K., Hara M., Takimoto H., Yorimitsu S., Takahashi I., Miyata A., Taniguchi S., Tokunaga Y., Gondo H., Niho Y., Nakao S., Kyo T., Dohy H., Kamada N., Harada M. Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia. Cancer Res., 59: 3931-3934, 1999.[Abstract/Free Full Text]
  12. Sun L., Heerema N., Crotty L., Wu X., Navara C., Vassilev A., Sensel M., Reaman G. H., Uckun F. M. Expression of dominant-negative and mutant isoforms of the antileukemic transcription factor Ikaros in infant acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA, 96: 680-685, 1999.[Abstract/Free Full Text]
  13. Sun L., Crotty M. L., Sensel M., Sather H., Navara C., Nachman J., Steinherz P. G., Gaynon P. S., Seibel N., Mao C., Vassilev A., Reaman G. H., Uckun F. M. Expression of dominant-negative Ikaros isoforms in T-cell acute lymphoblastic leukemia. Clin. Cancer Res., 5: 2112-2120, 1999.[Abstract/Free Full Text]
  14. Sun L., Goodman P. A., Wood C. M., Crotty M-L., Sensel M., Sather H., Navara C., Nachman J., Steinherz P. G., Gaynon P. S., Seibel N., Vassilev A., Juran B. D., Reaman G. H., Uckun F. M. Expression of aberrantly spliced oncogenic Ikaros isoforms in childhood acute lymphoblastic leukemia. J. Clin. Oncol., 17: 3753-3766, 1999.[Abstract/Free Full Text]
  15. Ishimaru F., Mari B., Shipp M. A. The type 2 CD10/neutral endopeptidase 24. 11 promoter: functional characterization and tissue-specific regulation by CBF/NF-Y isoforms. Blood, 89: 4136-4145, 1997.[Abstract/Free Full Text]
  16. Hayashi H., Ishimaru F., Fujita T., Tsurumi N., Tsuda T., Kimura I. Molecular genetic survey of five Japanese families with high-molecular-weight kininogen deficiency. Blood, 75: 1296-1304, 1990.[Abstract/Free Full Text]
  17. Avitahl N., Winandy S., Friedrich C., Jones B., Ge Y., Georgopoulos K. Ikaros sets thresholds for T cell activation and regulates chromosome propagation. Immunity, 10: 333-343, 1999.[Medline]
  18. Kim J., Sif S., Jones B., Jackson A., Koipally J., Heller E., Winandy S., Viel A., Sawyer A., Ikeda T., Kingston R., Georgopoulos K. Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity, 10: 345-355, 1999.[Medline]
  19. Gelmetti V., Zhang J., Fanelli M., Minucci S., Pelicci P. G., Lazar M. A. Aberrant recruitment of the nuclear receptor corepressor-histone deacetylases complex by the acute myeloid leukemia fusion partner ETO. Mol. Cell. Biol., 18: 7185-7191, 1998.[Abstract/Free Full Text]
  20. Melnick A. M., Westendorf J. J., Polinger A., Carlile G. W., Arai S., Ball H. J., Lutterbach B., Hiebert S. W., Licht J. D. The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein. Mol. Cell. Biol., 20: 2075-2086, 2000.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Cancer Res.Home page
S. Loeper, S. L. Asa, and S. Ezzat
Ikaros Modulates Cholesterol Uptake: A Link between Tumor Suppression and Differentiation
Cancer Res., May 15, 2008; 68(10): 3715 - 3723.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Antica, L. Cicin-Sain, S. Kapitanovic, M. Matulic, S. Dzebro, and M. Dominis
Aberrant Ikaros, Aiolos, and Helios expression in Hodgkin and non-Hodgkin lymphoma
Blood, March 15, 2008; 111(6): 3296 - 3297.
[Full Text] [PDF]

Home page
 BloodHome page
Z. Zhang, C. S. Swindle, J. T. Bates, R. Ko, C. V. Cotta, and C. A. Klug
Expression of a non-DNA-binding isoform of Helios induces T-cell lymphoma in mice
Blood, March 1, 2007; 109(5): 2190 - 2197.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. Ezzat, R. Mader, S. Fischer, S. Yu, C. Ackerley, and S. L. Asa
An essential role for the hematopoietic transcription factor Ikaros in hypothalamic-pituitary-mediated somatic growth
PNAS, February 14, 2006; 103(7): 2214 - 2219.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
A. Dumortier, R. Jeannet, P. Kirstetter, E. Kleinmann, M. Sellars, N. R. dos Santos, C. Thibault, J. Barths, J. Ghysdael, J. A. Punt, et al.
Notch Activation Is an Early and Critical Event during T-Cell Leukemogenesis in Ikaros-Deficient Mice
Mol. Cell. Biol., January 1, 2006; 26(1): 209 - 220.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. P. Tschan, K. M. Fischer, V. S. Fung, F. Pirnia, M. M. Borner, M. F. Fey, A. Tobler, and B. E. Torbett
Alternative Splicing of the Human Cyclin D-binding Myb-like Protein (hDMP1) Yields a Truncated Protein Isoform That Alters Macrophage Differentiation Patterns
J. Biol. Chem., October 31, 2003; 278(44): 42750 - 42760.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
K. J. Payne, G. Huang, E. Sahakian, J. Y. Zhu, N. S. Barteneva, L. W. Barsky, M. A. Payne, and G. M. Crooks
Ikaros Isoform X Is Selectively Expressed in Myeloid Differentiation
J. Immunol., March 15, 2003; 170(6): 3091 - 3098.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
R. M. Thomas, K. Haleem, A. B. Siddique, W. J. Simmons, N. Sen, D.-J. Zhang, and V. K. Tsiagbe
Regulation of Mouse Mammary Tumor Virus env Transcriptional Activator Initiated Mammary Tumor Virus Superantigen Transcripts in Lymphomas of SJL/J Mice: Role of Ikaros, Demethylation, and Chromatin Structural Change in the Transcriptional Activation of Mammary Tumor Virus Superantigen
J. Immunol., January 1, 2003; 170(1): 218 - 227.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
K. Nishii, N. Katayama, and H. Shiku
Adult acute myeloid leukemia cells do not express nonfunctional Ikaros isoforms
Blood, October 16, 2002; 100(9): 3436 - 3436.
[Full Text] [PDF]

Home page
 BloodHome page
F. Ishimaru, T. Yagi, S. Hibi, M. Takanashi, G. Kano, Y. Tabata, T. Imamura, T. Inaba, A. Morimoto, S. Todo, et al.
Expression of Ikaros isoforms in patients with acute myeloid leukemia
Blood, July 30, 2002; 100(4): 1511 - 1513.
[Full Text] [PDF]

Home page
 Cancer Res.Home page
A. Karlsson, P. Soderkvist, and S.-M. Zhuang
Point Mutations and Deletions in the Znfn1a1/Ikaros Gene in Chemically Induced Murine Lymphomas
Cancer Res., May 1, 2002; 62(9): 2650 - 2653.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nakase, K.
Right arrow Articles by Harada, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nakase, K.
Right arrow Articles by Harada, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online