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

Auer, Franziska; Ingenhag, Deborah; Pinkert, Stefan; Kracker, Sven; Hacein‐Bey‐Abina, Salima; Cavazzana, Marina; Gombert, Michael; Martín-Lorenzo, Alberto; Lin, Mao; Vicente-Dueñas, Carolina; Sánchez-Garcı́a, Isidro; Hauer, Julia

doi:10.18632/oncotarget.20563

Cited by 6 publications

(3 citation statements)

References 46 publications

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“…Leukemia caused by PU.1/Spi-B deletion strongly resembles fraction C large pre-B cells (Batista et al, 2018; Sokalski et al, 2011). We speculate that if driver mutations are induced by dysregulated AID in fraction B, such mutations would be positively selected by proliferation in fraction C. In support of this possibility, AID has been shown to be expressed in human and mouse pro-B cells (Auer et al, 2017; Cantaert et al, 2015). These results suggest that PU.1 is involved in the constraint of Aicda transcription in pro-B cells.…”

Section: Discussionmentioning

confidence: 79%

Negative regulation of Activation-Induced Cytidine Deaminase gene transcription in developing B cells by a PU.1-interacting intronic region

MacKenzie,

Sams,

Lin

et al. 2024

Preprint

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Activation-induced cytidine deaminase (AID, encoded byAicda) plays a key role in somatic hypermutation and class switch recombination in germinal center B cells. However, off-target effects of AID are implicated in human leukemia and lymphoma. A mouse model of precursor B cell acute lymphoblastic leukemia driven by deletion of the related transcription factors PU.1 and Spi-B revealed C->T transition mutations compatible with being induced by AID. Therefore, we hypothesized that PU.1 negatively regulatesAicdaduring B cell development.AicdamRNA transcript levels were increased in leukemia cells and preleukemic bone marrow pre-B cells lacking PU.1 and/or Spi-B, relative to wild type cells. Using chromatin immunoprecipitation, PU.1 was found to interact with a negative regulatory region (R2-1) within the first intron ofAicda. CRISPR-Cas9-induced mutagenesis of R2-1 in cultured pre-B cells resulted in upregulation ofAicdain response to lipopolysaccharide stimulation. Mutation of the PU.1 interaction site and neighboring sequences resulted in reduced repressive ability of R2-1 in transient transfection analysis followed by luciferase assays. These results show that a PU.1-interacting intronic region negatively regulatesAicdatranscription in developing B cells.

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Section: Discussionmentioning

confidence: 79%

Negative regulation of Activation-Induced Cytidine Deaminase gene transcription in developing B cells by a PU.1-interacting intronic region

MacKenzie,

Sams,

Lin

et al. 2024

Preprint

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“…In particular, our analysis focused on R653H, V670A, and T844M mutations in Jak3 . Jak3 R653H and V670A mutations were recently observed in B-ALL generated in activation-induced cytidine deaminase (AID) deficient mice 49 . Human equivalents of Jak3 R653H and V670A have been described in human ALL (R657Q, V674F), and furthermore have been shown to function by activation of proliferation in response to interleukin-7 50 .…”

Section: Discussionmentioning

confidence: 99%

Deletion of genes encoding PU.1 and Spi-B leads to B cell acute lymphoblastic leukemia associated with driver mutations in Janus Kinases

Lim

Laramée

et al. 2018

Preprint

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words) 20Precursor B-cell acute lymphoblastic leukemia (B-ALL) is associated with recurrent mutations that occur 21 in cancer-initiating cells. There is a need to understand how spontaneous driver mutations influence clonal 22 evolution in leukemia. The ETS-transcription factors PU.1 and Spi-B (encoded by Spi1 and Spib) execute 23 a critical role in B cell development and serve as complementary tumour suppressors by opposing the 24 proliferative events mediated by IL-7R signaling. Here, we used a mouse model to conditionally delete 25 Spi1 and Spib genes in developing B cells. These mice developed B-ALL with a median time to euthanasia 26 of 18 weeks. We performed RNA and whole-exome sequencing (WES) on leukemias isolated from Mb1-27CreΔPB mice and identified single-nucleotide variants (SNVs) in Jak1, Jak3 and Ikzf3 genes, resulting in 28 amino acid changes and in the gain of early stop-codons. JAK3 mutations resulted in amino acid 29 substitutions located in the pseudo-kinase (R653H, V670A) and in the kinase (T844M) domains. 30 Introduction of these mutations into wild-type pro-B cells conferred survival and proliferation advantages. 31We conclude that mutations in Janus kinases represent secondary drivers of leukemogenesis in the absence 32 of Spi-B and PU.1 transcription factors. This mouse model represents an useful tool to study clonal 33 evolution and tumour heterogeneity in B-ALL. 34 Introduction 35Acute lymphoblastic leukemia is the most common type of childhood cancer, with approximately 36 6000 new cases diagnosed in the United States each year 1 . Most leukemias originate within the B cell 37 rather than the T cell lineage 2,3 . Precursor B cell acute lymphoblastic leukemia (pre-B-ALL) is a disease 38 that is revealed by the presence of transformed precursor B cells in the blood, bone marrow, and tissues; 39 and is most common in 1-5 year old patients 4 . Most pre-B-ALL cases are associated with genetic 40 abnormalities that include chromosomal translocations or point mutations. In pre-B-ALL, up to two thirds 41 of genes with point mutations encode transcriptional regulators such as Pax-5, Ikaros, or EBF1 3 . Pre-B-42 ALL cells are frequently arrested at an early stage of development, express interleukin-7 receptor (IL7R), 43and have high levels of Janus Kinase (JAK)-STAT signaling to sustain survival and proliferation [5][6][7] . 44Activating mutations of the IL7R gene have been described in human pre-B-ALL 8 . JAK and IL7R 45 mutations are frequent in several subtypes of pre-B-ALL including the recently described disease Ph-like 46 leukemia 9,10 . In summary, mutations that activate cytokine signaling, and impair differentiation, function 47 as driver mutations in pre-B-ALL. 48 PU.1 (encoded by SPI1) and Spi-B (encoded SPIB in mice) are transcription factors of the E26-49 transformation-specific (ETS) family 11 . These two proteins share a conserved DNA binding domain and 50 interact with an overlapping set of DNA binding sites within the genome 12 . PU.1 and Spi-B complement 51 one anothers function...

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“…It has been suggested that DNM2 plays a major role in the internalization of IL7R, TCR, and Notch ligand Delta like 1 (DIl-1), thereby triggering the development of ALL [110]. Recently, somatic mutations of DNM2 were identified in pro-B ALL, with all of the mutant variants centric to the middle domain [111]. Loss of functional mutations in DNM2 has resulted in the increase of IL7R cell surface expression in a Lmo2 transgenic T-ALL mouse model [112].…”

Section: Dynamin 2 (Dnm2)mentioning

confidence: 99%

Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia

Dhanyamraju

Iyer

Smink

et al. 2020

IJMS

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Regulation of oncogenic gene expression by transcription factors that function as tumor suppressors is one of the major mechanisms that regulate leukemogenesis. Understanding this complex process is essential for explaining the pathogenesis of leukemia as well as developing targeted therapies. Here, we provide an overview of the role of Ikaros tumor suppressor and its role in regulation of gene transcription in acute leukemia. Ikaros (IKZF1) is a DNA-binding protein that functions as a master regulator of hematopoiesis and the immune system, as well as a tumor suppressor in acute lymphoblastic leukemia (ALL). Genetic alteration or functional inactivation of Ikaros results in the development of high-risk leukemia. Ikaros binds to the specific consensus binding motif at upstream regulatory elements of its target genes, recruits chromatin-remodeling complexes and activates or represses transcription via chromatin remodeling. Over the last twenty years, a large number of Ikaros target genes have been identified, and the role of Ikaros in the regulation of their expression provided insight into the mechanisms of Ikaros tumor suppressor function in leukemia. Here we summarize the role of Ikaros in the regulation of the expression of the genes whose function is critical for cellular proliferation, development, and progression of acute lymphoblastic leukemia.

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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

Cited by 6 publications

References 46 publications

Negative regulation of Activation-Induced Cytidine Deaminase gene transcription in developing B cells by a PU.1-interacting intronic region

Negative regulation of Activation-Induced Cytidine Deaminase gene transcription in developing B cells by a PU.1-interacting intronic region

Deletion of genes encoding PU.1 and Spi-B leads to B cell acute lymphoblastic leukemia associated with driver mutations in Janus Kinases

Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia

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