A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1

Vijayakrishnan, Jayaram; Kumar, Rajiv; Henrion, Marc; Moorman, Anthony V.; Rachakonda, P. Sivaramakrishna; Hosen, Ismail; Filho, Miguel Inácio da Silva; Holroyd, Amy; Dobbins, Sara E.; Koehler, Rolf; Thomsen, Hauke; Irving, Julie; Allan, James M.; Lightfoot, T.; Roman, Eve; Kinsey, Sally; Sheridan, Eamonn; Thompson, Pamela; Hoffmann, Per; Nöthen, Markus M.; Jöckel, Karl Heinz; Greaves, Mel; Harrison, Christine J.; Bartram, Claus R.; Schrappe, Martin; Stanulla, Martin; Hemminki, Kari; Houlston, Richard S.

doi:10.1038/leu.2016.271

Cited by 74 publications

(75 citation statements)

References 55 publications

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“…Among the E/R+ TF network, ELK3 and SP4 have been reported to confer risk of leukemia development in GWAS studies [48,49]. Previous expression quantitative trait loci data from mature B lymphoid cells indicated that the ELK3 risk variant associates with its lower expression [48]. This contrasts the data obtained here where high expression was seen in E/R+ scRNA-seq data, which we confirmed by bulk gene expression data comparing across hematologic malignancies [50].…”

Section: Single Cell Profiling Techniques Have Challenged How We Defisupporting

confidence: 71%

“…5a) across a large microarray gene expression dataset [50] (Hemap, N=9544, with 1304 pre-B-ALL samples). The ETS-factor ELK3 and SP4 have been implicated by genome-wide association (GWAS) studies as risk loci for pediatric pre-B-ALL [48,49]. Based on the bulk transcriptomes, we could validated both to be expressed in B-ALL, with highest proportion detected in the E/R+ subtype (red arrow), as shown comparing hematologic malignancies on the t-SNE plot of Hemap samples ( Fig.…”

Section: The Leukemic Regulatory Program Reveals Cell State Infidelitmentioning

confidence: 91%

Section: Single Cell Profiling Techniques Have Challenged How We Defimentioning

confidence: 99%

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Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1 positive pediatric leukemia identifies drug-targetable transcription factor activities

Mehtonen

Teppo

Lahnalampi

et al. 2020

Preprint

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Tight regulatory loops orchestrate commitment to B-cell fate within bone marrow. Genetic lesions in this gene regulatory network underlie the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). The initial genetic hits, including the common translocation that fuses ETV6 and RUNX1 genes, lead to arrested cell differentiation. Here, we aimed to characterize transcription factor activities along the B-lineage differentiation trajectory as a reference to characterize the aberrant cell states present in leukemic bone marrow, and to identify those transcription factors that maintain cancer-specific cell states for more precise therapeutic intervention.We compared normal B-lineage differentiation and in vivo leukemic cell states using single cell RNA-sequencing (scRNA-seq) and several complementary genomics profiles. Based on statistical tools for scRNA-seq, we benchmarked a workflow to resolve transcription factor activities and gene expression distribution changes in healthy bone marrow lymphoid cell states. We compared these to ALL bone marrow at diagnosis and in vivo during chemotherapy, focusing on leukemias carrying the ETV6-RUNX1 fusion.We show that lymphoid cell transcription factor activities uncovered from bone marrow scRNA-seq have high correspondence with independent ATAC- and ChIP-seq data. Using this comprehensive reference for regulatory factors coordinating B-lineage differentiation, our analysis of ETV6-RUNX1-positive ALL cases revealed elevated activity of multiple ETS-transcription factors in leukemic cells states, including the leukemia genome-wide association study hit ELK3. The accompanying gene expression changes associated with natural killer cell inactivation and depletion in the leukemic immune microenvironment. Moreover, our results suggest that the abundance of G1 cell cycle state at diagnosis and lack of differentiation-associated regulatory network changes during induction chemotherapy represent features of chemoresistance. To target the leukemic regulatory program and thereby overcome treatment-resistance, we show that selective inhibitors of ETS-transcription factors could effectively reduce cell viability.Our data provide a detailed picture of the transcription factor activities that characterize both normal B-lineage differentiation and those acquired in leukemic bone marrow and provide a rational basis for new treatment strategies targeting the immune microenvironment and the active regulatory network in leukemia.

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Section: Single Cell Profiling Techniques Have Challenged How We Defisupporting

confidence: 71%

Section: The Leukemic Regulatory Program Reveals Cell State Infidelitmentioning

confidence: 91%

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Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1 positive pediatric leukemia identifies drug-targetable transcription factor activities

Mehtonen

Teppo

Lahnalampi

et al. 2020

Preprint

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“…Interestingly in children the CRLF2/IL7RA subtype occurs later than the other genotypic subtypes of ALL 65 . Recently, gene-wide association studies have discovered several relatively common SNPs conferring a higher risk for childhood ALL 45,47,52,[66][67][68] . Strikingly, the genotype of the specific CB the transduction of which resulted in BCP-ALL, revealed heterozygosity for five predisposing SNPs scattered across four of these genes.…”

Section: Discussionmentioning

confidence: 99%

An instructive role for IL7RA in the development of human B-cell precursor leukemia

Geron

Savino

Tal

et al. 2020

Preprint

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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is preceded by a clinically silent preleukemia. Experimental models that authentically re-capitulate disease initiation and progression in human cells are lacking. We previously described activating mutations in interleukin 7 receptor alpha (IL7RA) that are associated with the poor-prognosis Philadelphialike (Ph-like) subtype of BCP-ALL. Whether IL7RA signaling has a role in initiation of human BCP-ALL is unknown. IL7RA is essential for mouse B-cell development; however, patients with truncating IL7RA germline mutations develop normal mature B-cell populations. Herein, we explore the consequences of aberrant IL7RA signaling activation in human hematopoietic progenitors on malignant B-cell development. Transplantation of human cord-blood hematopoietic progenitors transduced with activated mutant IL7RA into NOD/LtSz-scid IL2Rγ null mice resulted in B-cell differentiation arrest with aberrant expression of CD34 + and persistence of pro-B cells that survive despite failing to achieve productive rearrangement of immunoglobulin V(D)J gene segments. Activation of IL7RA signaling enhanced self-renewal and facilitated the development of a BCP-ALL in secondary transplanted mice. The development of leukemia was associated with spontaneous acquired deletions in CDKN2A/B and IKZF1 similar to what is observed in Ph-like BCP-ALL in humans. Single cell gene expression analysis suggested that pre-leukemic cells resided within a subpopulation of early B-cell precursors with CD34 + CD10 high CD19 low immunophenotype. The development of a bona fide BCP-ALL from IL7RA transduced cells supports the hypothesis that aberrant activation of the IL7RA pathway in human B-cell lineage progenitors has an instructive role by creating a pre-leukemic state which is vulnerable to transformation. These are the first demonstrations of a role for IL7RA in human B-cell differentiation and of a de-novo Phlike BCP-ALL development from normal human hematopoietic progenitors in vivo.

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“…Genome-wide association studies have identified common genetic variants associated with ALL risk. [2][3][4][5][6][7][8] Recent studies of familial ALL have revealed rare predisposing germline mutations in the hematopoietic regulator genes PAX5, SH2B3, ETV6, and IKZF1, [9][10][11][12][13][14][15] and next-generation sequencing in large numbers of de novo childhood ALL patients has identified at least 4% with likely functional germline mutations. 16,17 Elucidating the genetic component of ALL will be essential for risk stratification, prevention, and early detection of disease.…”

Section: Introductionmentioning

confidence: 99%

Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children

Smith

Lavoie

Walsh

et al. 2019

Genes Chromosomes & Cancer

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High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD‐ALL patients from the California Childhood Leukemia Study via targeted sequencing of cancer‐relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional six patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (<0.01% allele frequency in the Exome Aggregation Consortium, ExAC) and predicted functional (scaled CADD score ≥ 20) in known or potential ALL predisposition genes (SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9). Three additional patients carried rare and predicted damaging germline mutations in GAB2, a known activator of the ERK/MAPK and PI3K/AKT pathways and binding partner of PTPN11‐encoded SHP2. The frequency of rare and predicted functional germline GAB2 mutations was significantly higher in our patients (2.6%) than in ExAC (0.28%, P = 4.4 × 10−3), an observation that was replicated in ALL patients from the TARGET project (P = .034). We cloned patient GAB2 mutations and expressed mutant proteins in HEK293 cells and found that frameshift mutation P621fs led to reduced SHP2 binding and ERK1/2 phosphorylation but significantly increased AKT phosphorylation, suggesting possible RAS‐independent leukemogenic effects. Our results support a significant contribution of rare, high penetrance germline mutations to HD‐ALL etiology, and pinpoint GAB2 as a putative novel ALL predisposition gene.

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A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1

Cited by 74 publications

References 55 publications

Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1 positive pediatric leukemia identifies drug-targetable transcription factor activities

Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1 positive pediatric leukemia identifies drug-targetable transcription factor activities

An instructive role for IL7RA in the development of human B-cell precursor leukemia

Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children

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