title: Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis.
abstract: Notch receptors are conserved regulators of cell fate and have been implicated in the regulation of T cell differentiation and lymphomagenesis. However, neither the generality of Notch involvement in leukemia, nor the molecules with which Notch may interact have been clarified. Recently, we showed that transgenic mice expressing the constitutively active intracellular domain of Notch3 in thymocytes and T cells developed early and aggressive T cell neoplasias. Although primarily splenic, the tumors sustained features of immature thymocytes, including expression of pTalpha, a defining component of the pre T cell receptor, known to be a potent signaling complex provoking thymocyte survival, proliferation, and activation. Thus, enforced expression of Notch3, which is ordinarily down-regulated as thymocytes mature, may sustain pre T cell receptor expression, causing dysregulated hyperplasia. This hypothesis has been successfully tested in this article by the observation that deletion of pTalpha in Notch3 transgenic mice abrogates tumor development, indicating a crucial role for pTalpha in T cell leukemogenesis. Parallel observations were made in humans, in that all T cell acute lymphoblastic leukemias examined showed expression of Notch3 and of the Notch target gene HES-1, as well as of pTalpha a and b transcripts, whereas the expression of all these genes was dramatically reduced or absent in remission. Together, these results suggest that the combined expression of Notch3 and pTalpha sustains T cell leukemogenesis and may represent pathognomonic molecular features of human T-ALL.
authors.affiliation: Department of Experimental Medicine and Pathology, University La Sapienza, Viale Regina Elena 324, 00161 Roma, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Bellavia
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Campese
authors.forename: Saula
authors.initials: S
authors.lastname: Checquolo
authors.forename: Anna
authors.initials: A
authors.lastname: Balestri
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.forename: Urban
authors.initials: U
authors.lastname: Lendahl
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Fehling
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Hayday
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Harald
authors.initials: H
authors.lastname: von Boehmer
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D005434:Flow Cytometry; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D016130:Immunophenotyping; D015458:Leukemia, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014157:Transcription Factors
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C489734:Hes1 protein, mouse; C497761:NOTCH1 protein, human; C499374:NOTCH3 protein, human; C497762:Notch1 protein, mouse; C499373:Notch3 protein, mouse; C090377:pre-T cell receptor alpha; C073572:Notch4 protein, mouse; C078493:HES1 protein, human