Loss of P19Arf in a Rag1(-/-) B-cell Precursor Population Initiates Acute B-lymphoblastic Leukemia

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2011 May 31

PMID 21622646

Citations 7

Authors

Julia Hauer

Charles Mullighan

Estelle Morillon

Gary Wang

Julie Bruneau

Nicole Brousse

Marc Lelorch

Serge Romana

Amine Boudil

Daniela Tiedau

Sven Kracker

Frederic D Bushmann

Arndt Borkhardt

Alain Fischer

Salima Hacein-Bey-Abina

Marina Cavazzana-Calvo

Affiliations

Soon will be listed here.

Abstract

In human B-acute lymphoblastic leukemia (B-ALL), RAG1-induced genomic alterations are important for disease progression. However, given that biallelic loss of the RAG1 locus is observed in a subset of cases, RAG1's role in the development of B-ALL remains unclear. We chose a p19Arf(-/-)Rag1(-/-) mouse model to confirm the previously published results concerning the contribution of CDKN2A (p19ARF /INK4a) and RAG1 copy number alterations in precursor B cells to the initiation and/or progression to B-acute lymphoblastic leukemia (B-ALL). In this murine model, we identified a new, Rag1-independent leukemia-initiating mechanism originating from a Sca1(+)CD19(+) precursor cell population and showed that Notch1 expression accelerates the cells' self-renewal capacity in vitro. In human RAG1-deficient BM, a similar CD34(+)CD19(+) population expressed p19ARF. These findings suggest that combined loss of p19Arf and Rag1 results in B-cell precursor leukemia in mice and may contribute to the progression of precursor B-ALL in humans.

Citing Articles

Constitutive Ras signaling and inactivation cooperate during the development of B-ALL in mice.

Sewastianik T, Jiang M, Sukhdeo K, Patel S, Roberts K, Kang Y Blood Adv. 2018; 1(25):2361-2374.

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Activation-induced cytidine deaminase prevents pro-B cell acute lymphoblastic leukemia by functioning as a negative regulator in Rag1 deficient pro-B cells.

Auer F, Ingenhag D, Pinkert S, Kracker S, Hacein-Bey-Abina S, Cavazzana M Oncotarget. 2017; 8(44):75797-75807.

PMID: 29100269 PMC: 5652663. DOI: 10.18632/oncotarget.20563.

Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients.

Scheijen B, Boer J, Marke R, Tijchon E, van Ingen Schenau D, Waanders E Haematologica. 2016; 102(3):541-551.

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Genetically engineered mouse models of human B-cell precursor leukemias.

Hauer J, Borkhardt A, Sanchez-Garcia I, Cobaleda C Cell Cycle. 2014; 13(18):2836-46.

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Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011.

Olsson L, Castor A, Behrendtz M, Biloglav A, Forestier E, Paulsson K Leukemia. 2013; 28(2):302-10.

PMID: 23823658 DOI: 10.1038/leu.2013.206.

References

Nepal R, Zaheen A, Basit W, Li L, Berger S, Martin A . AID and RAG1 do not contribute to lymphomagenesis in Emu c-myc transgenic mice. Oncogene. 2008; 27(34):4752-6. DOI: 10.1038/onc.2008.111. View

le Viseur C, Hotfilder M, Bomken S, Wilson K, Rottgers S, Schrauder A . In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties. Cancer Cell. 2008; 14(1):47-58. PMC: 2572185. DOI: 10.1016/j.ccr.2008.05.015. View

Nacht M, Jacks T . V(D)J recombination is not required for the development of lymphoma in p53-deficient mice. Cell Growth Differ. 1998; 9(2):131-8. View

Kannan S, Fang W, Song G, Mullighan C, Hammitt R, McMurray J . Notch/HES1-mediated PARP1 activation: a cell type-specific mechanism for tumor suppression. Blood. 2011; 117(10):2891-900. PMC: 3062299. DOI: 10.1182/blood-2009-12-253419. View

Mullighan C, Phillips L, Su X, Ma J, Miller C, Shurtleff S . Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science. 2008; 322(5906):1377-80. PMC: 2746051. DOI: 10.1126/science.1164266. View

Lagresle-Peyrou C, Yates F, Malassis-Seris M, Hue C, Morillon E, Garrigue A . Long-term immune reconstitution in RAG-1-deficient mice treated by retroviral gene therapy: a balance between efficiency and toxicity. Blood. 2005; 107(1):63-72. DOI: 10.1182/blood-2005-05-2032. View

Wang G, Garrigue A, Ciuffi A, Ronen K, Leipzig J, Berry C . DNA bar coding and pyrosequencing to analyze adverse events in therapeutic gene transfer. Nucleic Acids Res. 2008; 36(9):e49. PMC: 2396413. DOI: 10.1093/nar/gkn125. View

Mullighan C, Goorha S, Radtke I, Miller C, Coustan-Smith E, Dalton J . Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007; 446(7137):758-64. DOI: 10.1038/nature05690. View

Williams R, den Besten W, Sherr C . Cytokine-dependent imatinib resistance in mouse BCR-ABL+, Arf-null lymphoblastic leukemia. Genes Dev. 2007; 21(18):2283-7. PMC: 1973142. DOI: 10.1101/gad.1588607. View

10.

Difilippantonio M, Zhu J, Chen H, Meffre E, Nussenzweig M, Max E . DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature. 2000; 404(6777):510-4. PMC: 4721590. DOI: 10.1038/35006670. View

11.

Vanasse G, Concannon P, Willerford D . Regulated genomic instability and neoplasia in the lymphoid lineage. Blood. 1999; 94(12):3997-4010. View

12.

Maillard I, Fang T, Pear W . Regulation of lymphoid development, differentiation, and function by the Notch pathway. Annu Rev Immunol. 2005; 23:945-74. DOI: 10.1146/annurev.immunol.23.021704.115747. View

13.

Kojika S, Griffin J . Notch receptors and hematopoiesis. Exp Hematol. 2001; 29(9):1041-52. DOI: 10.1016/s0301-472x(01)00676-2. View

14.

Mullighan C, Su X, Zhang J, Radtke I, Phillips L, Miller C . Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009; 360(5):470-80. PMC: 2674612. DOI: 10.1056/NEJMoa0808253. View

15.

Signer R, Montecino-Rodriguez E, Witte O, Dorshkind K . Aging and cancer resistance in lymphoid progenitors are linked processes conferred by p16Ink4a and Arf. Genes Dev. 2008; 22(22):3115-20. PMC: 2593609. DOI: 10.1101/gad.1715808. View

16.

Tanigaki K, Honjo T . Regulation of lymphocyte development by Notch signaling. Nat Immunol. 2007; 8(5):451-6. DOI: 10.1038/ni1453. View

17.

Noordzij J, de Bruin-Versteeg S, Verkaik N, Vossen J, de Groot R, Bernatowska E . The immunophenotypic and immunogenotypic B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins. Blood. 2002; 100(6):2145-52. View

18.

Cobaleda C, Schebesta A, Delogu A, Busslinger M . Pax5: the guardian of B cell identity and function. Nat Immunol. 2007; 8(5):463-70. DOI: 10.1038/ni1454. View

19.

Butler J, Nolan D, Vertes E, Varnum-Finney B, Kobayashi H, Hooper A . Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell. 2010; 6(3):251-64. PMC: 2866527. DOI: 10.1016/j.stem.2010.02.001. View

20.

Wang P, Young F, Chen C, Stevens B, Neering S, Rossi R . The biologic properties of leukemias arising from BCR/ABL-mediated transformation vary as a function of developmental origin and activity of the p19ARF gene. Blood. 2008; 112(10):4184-92. PMC: 2581986. DOI: 10.1182/blood-2008-02-142190. View