Radiation-Associated Loss of Heterozygosity at theZnfn1a1(Ikaros) Locus on Chromosome 11 in Murine Thymic Lymphomas

Abstract

Although information on the molecular pathways in radiation carcinogenesis is accumulating, the data are still relatively scanty. To find the tumor suppressor locus associated with radiation carcinogenesis, we determined the frequency and distribution of loss of heterozygosity (LOH) of X-ray-induced thymic lymphomas of B6C3F(1) mice using 58 microsatellite markers and compared the results with those for spontaneous lymphomas and N-ethylnitrosourea (ENU)-induced lymphomas. Based on the results, we describe a unique locus with frequent LOH in the centromeric region of chromosome 11 of X-ray-induced lymphomas. This locus has never been observed to be altered similarly in either ENU-induced or spontaneous lymphomas, suggesting radiation-specific molecular alteration. The LOH patterns of individual thymic lymphomas indicated that the common region of LOH was located within 1.6 cM between D11Mit62 and D11Mit204, a region syntenic to human chromosome 7p13. Linkage analysis revealed that the markers of the common LOH region were genetically linked to Ikaros (now known as Znfn1a1), a master gene of lymphopoiesis. Although the presence of radiation-associated LOH in other loci cannot be ruled out, these results suggest a novel molecular pathway in induction of thymic lymphomas by ionizing radiation.

Ikaros is a mutational target for lymphomagenesis in Mlh1-deficient mice

“…Thus, these mutations are closely linked to Mlh1 deficiency. We previously reported that Ikaros mutation spectrum is influenced by carcinogen, which causes different types of DNA damage (Shimada et al, 2000;Kakinuma et al, 2002Kakinuma et al, , 2005. The present result suggests that a balance (or distortion) of DNA repair systems is also an important determinant for the spectrum.…”

“…Dominant-negative Ikaros isoforms are reportedly expressed in human acute T-and B-lymphoblastic leukemia (ALL) and chronic myelogenous leukemia (CML) (Nakayama et al, 1999;Sun et al, 1999a, b). Others and we have reported not only the expression of dominant-negative isoforms but also null expression and point mutations in radiationand chemical-induced mouse T-cell lymphomas (Okano et al, 1999;Shimada et al, 2000;Kakinuma et al, 2002Kakinuma et al, , 2005Karlsson et al, 2002). Furthermore, homozygous null mice and mice heterozygous for the Ikaros dominant-negative isoforms or Ikaros Plstic mutants exhibit T-cell hyperproliferation and ultimately die of T-cell lymphomas (Winandy et al, 1995;Wang et al, 1996;Papathanasiou et al, 2003).…”

Ikaros is a critical target during simultaneous exposure to X‐rays and N‐ethyl‐N‐nitrosourea in mouse T‐cell lymphomagenesis

“…The method of induction of TL by X-rays and ENU has been described. 9,22 In brief, beginning at 4 weeks of age, female B6C3F1 mice were exposed weekly to whole-body Xrays at a dose of 0.8, 1.0 or 1.2 Gy for four consecutive weeks or were given ENU in drinking water for four consecutive weeks at a dose of 100 or 200 ppm as a single agent, or they were given both treatments simultaneously (Fig. 1a).…”

“…8 TLs with a Notch1 mutation in the HD domain, the PEST domain or both domains are shown. 9 The combined proportion of TLs carrying rearrangements and/or mutations is shown. *p < 0.05; **p < 0.01; ***p < 0.001.…”

La voie Notch au centre du mécanisme de leucémogenèse dans un modèle murin de leucémies T

“…Chez les patients atteints de LAL-T, l'activation de Notch est souvent associée à des mutations du gène Notch1 qui augmentent sa sensibilité au clivage par la γ-sécrétase (mutations du domaine d'hétérodimérisation), ou qui entraînent des troncations dans la partie carboxyterminale augmentant l'activité de cette protéine [ [3], un répresseur transcriptionnel de la famille des protéines à doigts de zinc [4]. Plusieurs études ont impliqué Ikaros comme un gène suppresseur de tumeurs pour les leucémies/lymphomes T. Ainsi, des pertes alléliques, ou des mutations ponctuelles conférant à Ikaros une action dominante négative sont fréquemment détectées dans des lymphomes thymiques murins induits par des agents mutagènes ou par irradiation [5][6][7] mutations ponctuelles dans les séquen-ces codant la région carboxy-terminale, induisant un décalage de phase conduisant à la délétion du domaine PEST (impliqué dans la stabilité de Notch1). De façon intéressante, ces mutations sont similaires à certaines de celles décrites dans les LAL-T humaines (Figure 2 > La peau est la première ligne de défense qui protège le corps de la déshydrata-tion, des blessures et des infections.…”