title: A mouse model for inducible overexpression of Prdm14 results in rapid-onset and highly penetrant T-cell acute lymphoblastic leukemia (T-ALL).
abstract: PRDM14 functions in embryonic stem cell (ESC) maintenance to promote the expression of pluripotency-associated genes while suppressing differentiation genes. Expression of PRDM14 is tightly regulated and typically limited to ESCs and primordial germ cells; however, aberrant expression is associated with tumor initiation in a wide variety of human cancers, including breast cancer and leukemia. Here, we describe the generation of a Cre-recombinase-inducible mouse model for the spatial and temporal control of Prdm14 misexpression [ROSA26 floxed-stop Prdm14 (R26PR)]. When R26PR is mated to either of two Cre lines, Mx1-cre or MMTV-cre, mice develop early-onset T-cell acute lymphoblastic leukemia (T-ALL) with median overall survival of 41 and 64 days for R26PR;Mx1-cre and R26PR;MMTV-cre, respectively. T-ALL is characterized by the accumulation of immature single-positive CD8 cells and their widespread infiltration. Leukemia is preceded by a dramatic expansion of cells resembling hematopoietic stem cells and lymphoid-committed progenitors prior to disease onset, accompanied by a blockage in B-cell differentiation at the early pro-B stage. Rapid-onset PRDM14-induced T-ALL requires factors that are present in stem and progenitor cells: R26PR;dLck-cre animals, which express Prdm14 starting at the double-positive stage of thymocyte development, do not develop disease. PRDM14-induced leukemic cells contain high levels of activated NOTCH1 and downstream NOTCH1 targets, including MYC and HES1, and are sensitive to pharmacological inhibition of NOTCH1 with the γ-secretase inhibitor DAPT. Greater than 50% of human T-ALLs harbor activating mutations in NOTCH1; thus, our model carries clinically relevant molecular aberrations. The penetrance, short latency and involvement of the NOTCH1 pathway will make this hematopoietic R26PR mouse model ideal for future studies on disease initiation, relapse and novel therapeutic drug combinations. Furthermore, breeding R26PR to additional Cre lines will allow for the continued development of novel cancer models.
authors.affiliation: Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Brandi L
authors.initials: BL
authors.lastname: Carofino
authors.forename: Bernard
authors.initials: B
authors.lastname: Ayanga
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Justice
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D051379:Mice; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C531066:Prdm14 protein, mouse; D016601:RNA-Binding Proteins; D014157:Transcription Factors
references.citation: Nature. 2010 Nov 11;468(7321):316-20
references.pmid: 20953172
references.citation: J Exp Med. 1996 May 1;183(5):2283-91
references.pmid: 8642337
references.citation: Cancer Res. 2013 Jan 15;73(2):930-41
references.pmid: 23161489
references.citation: Nat Genet. 2005 Aug;37(8):899-905
references.pmid: 16007089
references.citation: Annu Rev Med. 2007;58:267-84
references.pmid: 17002552
references.citation: Cancer Res. 2007 Oct 15;67(20):9649-57
references.pmid: 17942894
references.citation: Clin Cancer Res. 2008 Sep 1;14(17):5314-7
references.pmid: 18765521
references.citation: Immunity. 1999 Sep;11(3):299-308
references.pmid: 10514008
references.citation: Cancer Res. 2010 Apr 1;70(7):2770-8
references.pmid: 20215524
references.citation: J Immunol. 2005 Jun 1;174(11):6725-31
references.pmid: 15905512
references.citation: Oncogene. 2006 Oct 5;25(45):6092-100
references.pmid: 16652142
references.citation: Cell. 1996 Nov 1;87(3):483-92
references.pmid: 8898201
references.citation: Mod Pathol. 2010 Jul;23(7):1029-39
references.pmid: 20473280
references.citation: Nat Rev Immunol. 2008 May;8(5):380-90
references.pmid: 18421304
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D56-63
references.pmid: 23193274
references.citation: J Immunol. 2002 Aug 15;169(4):1817-21
references.pmid: 12165504
references.citation: EMBO Rep. 2013 Jul;14(7):629-37
references.pmid: 23670199
references.citation: Anal Biochem. 2011 May 1;412(1):92-5
references.pmid: 21255551
references.citation: Int Immunol. 2011 Jan;23(1):55-64
references.pmid: 21148236
references.citation: Methods Mol Biol. 2009;530:365-78
references.pmid: 19266338
references.citation: Oncogene. 2003 Oct 2;22(43):6764-73
references.pmid: 14555989
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14920-5
references.pmid: 14657333
references.citation: Clin Cancer Res. 2012 May 15;18(10):2754-67
references.pmid: 22589484
references.citation: Nat Genet. 2008 Aug;40(8):1016-22
references.pmid: 18622394
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Immunology. 2002 Dec;107(4):444-51
references.pmid: 12460189
references.citation: Stem Cells. 2013 Apr;31(4):682-92
references.pmid: 23280602
references.citation: Blood. 2011 Jun 30;117(26):7079-89
references.pmid: 21536859
references.citation: Cancers (Basel). 2012 Dec 1;4(4):1050-1066
references.pmid: 23487523
references.citation: Nat Rev Cancer. 2006 May;6(5):347-59
references.pmid: 16612405
references.citation: Zhongguo Fei Ai Za Zhi. 2010 Sep;13(9):867-72
references.pmid: 20840815
references.citation: Nat Struct Mol Biol. 2013 Mar;20(3):311-6
references.pmid: 23416945
references.citation: Transgenic Res. 2001 Dec;10(6):545-53
references.pmid: 11817542
references.citation: Cancer Res. 2006 Apr 1;66(7):3355-8, discussion 3358-9
references.pmid: 16585152
references.citation: Mol Cell Biol. 1999 Jul;19(7):5025-35
references.pmid: 10373552
references.citation: Genesis. 2007 Sep;45(9):593-605
references.pmid: 17868096
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3789-94
references.pmid: 9108056
references.citation: Nat Methods. 2009 Jul;6(7):493-5
references.pmid: 19525957
references.citation: Cell Stem Cell. 2012 Apr 6;10(4):425-39
references.pmid: 22482507
references.citation: Nat Rev Cancer. 2007 Sep;7(9):645-58
references.pmid: 17687385
references.citation: Science. 1995 Sep 8;269(5229):1427-9
references.pmid: 7660125
references.citation: J Oncol. 2012;2012:608406
references.pmid: 22927846
references.citation: J Virol. 1994 Mar;68(3):1293-300
references.pmid: 8107195
references.citation: Blood. 2002 Apr 1;99(7):2369-78
references.pmid: 11895769
references.citation: Biochem Biophys Res Commun. 2008 Mar 21;367(4):899-905
references.pmid: 18194669
references.citation: Nat Struct Mol Biol. 2011 Feb;18(2):120-7
references.pmid: 21183938
references.citation: Cancer Res. 2011 Apr 1;71(7):2706-17
references.pmid: 21324922
references.citation: Science. 2010 Feb 12;327(5967):879-83
references.pmid: 20093438
references.citation: Cancer Res. 2000 Aug 15;60(16):4519-25
references.pmid: 10969801
references.citation: Development. 2000 Nov;127(22):4949-58
references.pmid: 11044408
references.citation: Development. 2012 Jul;139(13):2267-82
references.pmid: 22669819
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Oncogene. 2011 Jun 23;30(25):2859-73
references.pmid: 21339739
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4508-13
references.pmid: 11917122
references.citation: Proc Natl Acad Sci U S A. 1985 Sep;82(17):5880-4
references.pmid: 2994051
references.citation: Annu Rev Immunol. 1987;5:621-69
references.pmid: 2885016
references.citation: J Exp Med. 2001 Jul 2;194(1):99-106
references.pmid: 11435476
references.citation: Blood. 2006 Jul 15;108(2):653-61
references.pmid: 16537801
references.citation: Methods Mol Biol. 2002;180:175-204
references.pmid: 11873650
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2361-5
references.pmid: 21262837
references.citation: Pathogenetics. 2008 Nov 03;1(1):3
references.pmid: 19014667
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5106-11
references.pmid: 20194733
references.citation: Blood. 2011 Oct 27;118(17):4646-56
references.pmid: 21828136