Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia

Srividya Swaminathan; Lars Klemm; Eugene Park; Elli Papaemmanuil; Anthony Ford; Soo-Mi Kweon; Daniel Trageser; Brian Hasselfeld; Nadine Henke; Jana Mooster; Huimin Geng; Klaus Schwarz; Scott C Kogan; Rafael Casellas; David G Schatz; Michael R Lieber; Mel F Greaves; Markus Müschen

doi:10.1038/ni.3160

Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia

Nat Immunol. 2015 Jul;16(7):766-774. doi: 10.1038/ni.3160. Epub 2015 May 18.

Authors

Srividya Swaminathan^#¹, Lars Klemm^#^{1

2}, Eugene Park^{1

3}, Elli Papaemmanuil³, Anthony Ford⁴, Soo-Mi Kweon⁵, Daniel Trageser⁵, Brian Hasselfeld⁵, Nadine Henke⁶, Jana Mooster⁶, Huimin Geng¹, Klaus Schwarz⁷, Scott C Kogan¹, Rafael Casellas⁸, David G Schatz⁹, Michael R Lieber⁵, Mel F Greaves⁴, Markus Müschen^{1

3}

Affiliations

¹ Department of Laboratory Medicine, University of California San Francisco, CA, 94143.
² University of Freiburg, Faculty of Biology, 79104 Freiburg, Germany.
³ Department of Haematology, University of Cambridge, Cambridge UK.
⁴ Centre for Evolution and Cancer, The Institute of Cancer Research, London UK.
⁵ University of Southern California, Los Angeles, CA.
⁶ Heinrich-Heine-Universität Düsseldorf, Germany.
⁷ Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
⁸ Genomics & Immunity, NIAMS, NIH, Bethesda, 20892, MD.
⁹ Yale University, New Haven, CT.

^# Contributed equally.

PMID: 25985233
PMCID: PMC4475638
DOI: 10.1038/ni.3160

Abstract

Childhood acute lymphoblastic leukemia (ALL) can often be traced to a pre-leukemic clone carrying a prenatal genetic lesion. Postnatally acquired mutations then drive clonal evolution toward overt leukemia. The enzymes RAG1-RAG2 and AID, which diversify immunoglobulin-encoding genes, are strictly segregated in developing cells during B lymphopoiesis and peripheral mature B cells, respectively. Here we identified small pre-BII cells as a natural subset with increased genetic vulnerability owing to concurrent activation of these enzymes. Consistent with epidemiological findings on childhood ALL etiology, susceptibility to genetic lesions during B lymphopoiesis at the transition from the large pre-BII cell stage to the small pre-BII cell stage was exacerbated by abnormal cytokine signaling and repetitive inflammatory stimuli. We demonstrated that AID and RAG1-RAG2 drove leukemic clonal evolution with repeated exposure to inflammatory stimuli, paralleling chronic infections in childhood.

MeSH terms

Adolescent
Animals
Antibody Diversity / genetics
Antibody Diversity / immunology
B-Lymphocytes / immunology*
B-Lymphocytes / metabolism
Child
Child, Preschool
Clonal Evolution / genetics
Clonal Evolution / immunology*
Cytidine Deaminase / genetics
Cytidine Deaminase / immunology
Cytidine Deaminase / metabolism
DNA-Binding Proteins / genetics
DNA-Binding Proteins / immunology
DNA-Binding Proteins / metabolism
Female
Flow Cytometry
Homeodomain Proteins / genetics
Homeodomain Proteins / immunology
Homeodomain Proteins / metabolism
Humans
Immunoblotting
Infant
Male
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Mice, Transgenic
Microscopy, Fluorescence
Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
Precursor Cells, B-Lymphoid / immunology*
Precursor Cells, B-Lymphoid / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured

Substances

DNA-Binding Proteins
Homeodomain Proteins
V(D)J recombination activating protein 2
RAG-1 protein
AICDA (activation-induced cytidine deaminase)
Cytidine Deaminase

Abstract

MeSH terms

Substances

Grants and funding