TY - JOUR
T1 - Loss of p19Arf in a Rag1-/- B-cell precursor population initiates acute B-lymphoblastic leukemia
AU - Hauer, Julia
AU - Mullighan, Charles
AU - Morillon, Estelle
AU - Wang, Gary
AU - Bruneau, Julie
AU - Brousse, Nicole
AU - Lelorc'h, Marc
AU - Romana, Serge
AU - Boudil, Amine
AU - Tiedau, Daniela
AU - Kracker, Sven
AU - Bushmann, Frederic D.
AU - Borkhardt, Arndt
AU - Fischer, Alain
AU - Hacein-Bey-Abina, Salima
AU - Cavazzana-Calvo, Marina
PY - 2011/7/21
Y1 - 2011/7/21
N2 - 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 ofCDKN2A(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-nitiating 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.
AB - 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 ofCDKN2A(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-nitiating 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.
UR - http://www.scopus.com/inward/record.url?scp=79960691203&partnerID=8YFLogxK
U2 - 10.1182/blood-2010-09-305383
DO - 10.1182/blood-2010-09-305383
M3 - Article
C2 - 21622646
AN - SCOPUS:79960691203
SN - 0006-4971
VL - 118
SP - 544
EP - 553
JO - Blood
JF - Blood
IS - 3
ER -
