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Blood, 15 January 2006, Vol. 107, No. 2, pp. 781-785. Prepublished online as a Blood First Edition Paper on September 15, 2005; DOI 10.1182/blood-2005-06-2553. This Article Abstract Full Text (PDF) Supplemental Table All Versions of this Article: 2005-06-2553v1 107/2/781    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by O'Neil, J. Articles by Look, A. T. Search for Related Content PubMed PubMed Citation Articles by O'Neil, J. Articles by Look, A. T. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Brief report Activating Notch1 mutations in mouse models of T-ALL Jennifer O'Neil, Jennifer Calvo, Keith McKenna, Veena Krishnamoorthy, Jon C. Aster, Craig H. Bassing, Frederick W. Alt, Michelle Kelliher, and A. Thomas Look From the Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Howard Hughes Medical Institute, The Children's Hospital, Department of Genetics, Harvard Medical School and The Center for Blood Research, Boston, MA.    Abstract Top Abstract Introduction Study design Results and discussion References   Recent studies have demonstrated that most patients with T-cell acute lymphocytic leukemia (T-ALL) have activating mutations in NOTCH1. We sought to determine whether these mutations are also acquired in mouse models of T-ALL. We sequenced the heterodimerization domain and the PEST domain of Notch1 in our mouse model of TAL1-induced leukemia and found that 74% of the tumors harbor activating mutations in Notch1. Cell lines derived from these tumors undergo G0/G1 arrest and apoptosis when treated with a -secretase inhibitor. In addition, we found activating Notch1 mutations in 31% of thymic lymphomas that occur in mice deficient for various combinations of the H2AX, Tp53, and Rag2 genes. Thus, Notch1 mutations are often acquired as a part of the molecular pathogenesis of T-ALLs that develop in mice with known predisposing genetic alterations. (Blood. 2006;107:781-785)    Introduction Top Abstract Introduction Study design Results and discussion References   TAL1 is a basic helix-loop-helix (bHLH) transcription factor that is normally expressed in hematopoietic cells, endothelial cells, and cells of the central nervous system. Through chromosomal translocation, interstitial deletion, or biallelic activation, TAL1 is misexpressed in thymocytes of 60% and 45% of pediatric and adult patients with T-cell acute lymphocytic leukemia (T-ALL), respectively.1,2 Improved results in the treatment of pediatric T-ALL have been achieved in recent years because of intensified chemotherapy regimens, leading to a 5-year event-free survival rate approaching 80%3,4; however, patients whose lymphoblasts overexpress the TAL1 oncogene have less favorable prognoses than do patients with activation of other oncogenes.5,6 Double-strand breaks occur in mammalian cells as a result of exposure to DNA-damaging agents such as ionizing radiation (IR) or during V(D)J recombination in lymphocytes. Many T-ALL tumors harbor chromosomal translocations or rearrangements that activate oncogenes or create oncogenic fusion genes.7 These translocations and rearrangements likely occur as a result of errors in the repair of double-strand breaks. The histone H2A variant, H2AX, plays a role in the cellular response to IR-induced double-strand breaks.8,9 H2AX deficiency alone causes only a modest predisposition to cancer; however, mice deficient for both H2AX and p53 rapidly develop T- and B-cell lymphomas and solid tumors, demonstrating that H2AX acts as a tumor suppressor in mice.10,11 The fact that human H2AX (H2AFX) maps to 11q23, a region that is frequently altered in human cancer, suggests that the human gene may also function as a tumor suppressor.10 The NOTCH genes encode single-pass transmembrane receptors that regulate apoptosis, proliferation, and cell fate determination in multicellular organisms. Binding of NOTCH ligands initiates a series of proteolytic cleavages in NOTCH1. The last of these cleavages, which is catalyzed by -secretase, results in the release of the intracellular domain of NOTCH1 (ICN), permitting it to translocate to the nucleus and form part of a multiprotein complex that regulates gene transcription.12 Recent work from our laboratories has revealed that activating mutations in NOTCH1 occur in more than 50% of human T-ALL.13 Previous studies have demonstrated that the Notch1 gene is a frequent site of retroviral insertional mutagenesis in mouse models of T-ALL14-17 (see also http://TCGD.ncifcrf.gov). To determine whether Notch mutations are acquired in mouse models of T-ALL, we sequenced the heterodimerization domain and the PEST domain of all 4 Notch genes in tumors from our previously established models of T-ALL.    Study design Top Abstract Introduction Study design Results and discussion References   Mice FVB/N Lck-Tal1 transgenic mice and Tal1/+HEB+/- mice have been previously described.18,19 Ink4a/Arf+/- mice were obtained from the MMHCC mouse repository20 and mated to Tal1 transgenic mice to obtain Tal1/+Ink4a/Arf+/- mice.24 129Sv/ev Tp53-/-, H2AX-/-, H2AX-/-Tp53-/-, and H2AX+/-Tp53-/- mice were described previously.10 RAG2-deficient mice21 were mated to the above mice to obtain H2AX-/-Tp53+/-RAG-/- and H2AX+/-Tp53-/-RAG-/- mice. Mutation detection Exons 26 and 27 of Notch1 were amplified using the following primers: exon 26 forward, 5'-ACGGGAGGACCTAACCAAAC-3'; exon 26 reverse, 5'-CAGCTTGGTCTCCAACACCT-3'; exon 27 forward, 5'-CGCTGAGTGCTAAACACTGG-3'; and exon 27 reverse, 5'-GTTTTGCCTGCATGTACGTC-3'. Exon 34 was amplified in 2 fragments using the following primers: forward 1, 5'-GCTCCCTCATGTACCTCCTG-3'; reverse 1, 5'-TAGTGGCCCCATCATGCTAT-3'; forward 2, 5'-ATAGCATGATGGGGCCACTA-3'; reverse 2, 5'-CTTCACCCTGACCAGGAAAA-3'. The products were direct sequenced at Agencourt Bioscience Corporation (Beverly, MA), and the results were analyzed using Mutation Surveyor (State College, PA). Gamma-secretase inhibitor treatment Murine Tal1 tumor cell lines either were treated with 1 µM DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-(S)-phenylglycine t-butyl ester) (catalog number 565770; Calbiochem, San Diego, CA) or were mock treated with DMSO for 6 days. The cells were fixed with 70% ethanol, stained with propidium iodide, and analyzed by flow cytometry. Western blotting Tal1 tumor cell lines were untreated or treated with 1 µM DAPT. Cell lysates were fractionated through sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and then transferred to PVDF. Intracellular Notch1 was detected by probing the blot with the V1744 antibody (Cell Signaling Technology, Beverly, MA). The blot was then stripped and reprobed with an anti--actin antibody (Sigma, St Louis, MO) to ensure equal loading. RT-PCR RNA was extracted from Tal1 tumor cells that were untreated or treated with DAPT using TRIzol (Invitrogen, Carlsbad, CA). cDNA was prepared with Superscript II reverse transcriptase (Invitrogen). Reverse transcription-polymerase chain reaction (RT-PCR) was then performed using primers specific for Deltex, Hes1, and GAPDH.22    Results and discussion Top Abstract Introduction Study design Results and discussion References   We sequenced the heterodimerization domain and the PEST domain of all 4 Notch genes in tumors from Tal1/+, Tal1/+HEB+/-, and Tal1/+Ink4a/Arf+/- mice. Of the 27 tumors we analyzed, we found activating mutations in the Notch1 gene in 20 (74%) samples (Table 1). One tumor had a point mutation in the heterodimerization domain leading to a leucine-to-proline change at residue 1668 (1679 in human NOTCH1). Point mutations causing identical leucine-to-proline substitutions have been observed in 4 patients with T-ALL.13 Most mutations that we detected in the mouse tumors were in the PEST domain. Here, as in the human cell lines and samples, we found insertions, deletions, and point mutations, resulting in premature stop codons and loss of the notch1 PEST domain. In contrast, we found no mutations in Notch2, Notch3, or Notch4. View this table: [in this window] [in a new window]   Table 1.. Activating Notch 1 mutations occur at a high frequency in mouse T-ALL   In addition to the Notch1 mutations found in tal1 transgenic mice, we also found Notch1 mutations in 9 of 29 (31%) of T-cell tumors that developed in H2AX-/-, Tp53-/-, H2AX-/-Tp53-/-, H2AX+/-Tp53-/-, Tp53-/-RAG-/-, H2AX-/-Tp53-/-RAG-/-, and H2AX-/-p53+/-RAG-/- mice. One tumor (455) had an alanine-to-proline missense mutation in the heterodimerization domain of notch1. This same mutation at the homologous residue in human NOTCH1 (1702) was also observed in one primary sample from a patient with T-ALL.13 However, as in the Tal1 transgenic mice, most of the mutations were in the PEST domain. These data indicate that Notch1 mutations are not specific to leukemias arising in Tal1 transgenic mice but that they arise in diverse T-ALL-prone backgrounds. Of note, Notch1 mutations are significantly more common in Tal1 transgenic mice than in mice that are heterozygous or deficient for Tp53 (P = .001), H2AX (P = .006), or RAG (P = .001) using a 2-tailed Fisher exact test. Because of the complex genotypes of the mice analyzed in this study, further experiments will be necessary to determine the individual contributions of Tp53, H2AX, or RAG deficiency to susceptibility to Notch1 mutations. The mutations we have found affecting full-length notch proteins in murine T-ALL are predicted to activate notch pathway signaling in way that is dependent on cellular -secretase activity. Therefore, to determine whether the tumor cells depend on notch signaling, we treated tumor cell lines derived from these mice with the -secretase inhibitor DAPT (Figure 1, Table S1; see the Supplemental Table link at the top of the online article, at the Blood website). After treatment of the cell lines with the inhibitor for 6 days, we found that most cell lines exhibited G0/G1 arrest, an increase in apoptosis, or both, as indicated by cells with 45% to 70% sub-G0/G1 DNA content (similar results were also seen after 3 days). In addition, we demonstrate that in sensitive and resistant cell lines, DAPT treatment inhibits the production of activated notch (Figure 1E) and the transcription of the notch target genes Deltex and Hes1 (Figure 1F). Some Tal1 tumor cell lines were resistant to the -secretase inhibitor treatment. Two of 4 -secretase-resistant cell lines did not have mutations in Notch1. Resistant cell lines with mutations in Notch1 have likely incurred additional mutations, rendering them independent of notch pathway signaling for growth and survival because DAPT treatment does decrease notch1 signaling in these cells. In fact, our previous studies have demonstrated that tumor 5146 displays constitutive NFB activation; therefore, it may be dependent on NFB signaling rather than on notch signaling for its growth and survival.23 One cell line was sensitive to the -secretase inhibitor but did not have a mutation in Notch1. In this case, we hypothesize that there might have been activating mutations in one or more other components of the notch signaling pathway. However, we cannot rule out the possibility that this cell line has a mutation in another substrate of -secretase. This work provides further evidence that Notch1 activation plays a key role in the pathogenesis of T-ALL in humans and in murine models and provides model systems incorporating clinically relevant oncogenes and tumor suppressors for testing therapeutics that target the NOTCH signaling pathway. View larger version (35K): [in this window] [in a new window]   Figure 1.. Cell lines derived from Tal1 tumors are sensitive to a -secretase inhibitor. Tal1 tumor cell lines were treated with 1 µM DAPT or DMSO (control) for 6 days, and the DNA content of propidium iodide-stained cell populations was determined by flow cytometry. (A-D) Numbers over the cell populations indicate the percentages of cells in sub-G0/G1, G0/G1, S, and G2/M phases. Tal1 tumor cells were untreated or treated with DAPT for 40 hours. (E) Western blot analysis using an antibody that specifically recognizes the activated form of notch1. A Tal1 T-ALL cell line was untreated or treated with DAPT for 24 or 48 hours. (F) RT-PCR analysis was performed with primers specific for Deltex, Hes1, and GAPDH.      Footnotes   Submitted June 28, 2005; accepted September 1, 2005. Prepublished online as Blood First Edition Paper, September 15, 2005; DOI 10.1182/blood-2005-06-2553. Supported by a Harvard Medical School Training Grant (J.O.) and grants from the NIH (F.W.A., M.K., and A.T.L.). M.K. and A.T.L. contributed equally to this work. The online version of this article contains a data supplement. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: A. Thomas Look, Department of Pediatric Oncology, Mayer Bldg, Rm 630, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: thomas_look{at}dfci.harvard.edu.    References Top Abstract Introduction Study design Results and discussion References   Ferrando AA, Look AT. Gene expression profiling in T-cell acute lymphoblastic leukemia. Semin Hematol. 2003;40: 274-280.[CrossRef][Medline] [Order article via Infotrieve] Ferrando AA, Herblot S, Palomero T, et al. Biallelic transcriptional activation of oncogenic transcription factors in T-cell acute lymphoblastic leukemia. 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[Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) Supplemental Table All Versions of this Article: 2005-06-2553v1 107/2/781    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by O'Neil, J. Articles by Look, A. T. Search for Related Content PubMed PubMed Citation Articles by O'Neil, J. Articles by Look, A. T. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Brief Reports Social Bookmarking                   What's this?

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