Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia

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

doi:10.1038/ni.3160

Cited by 180 publications

(213 citation statements)

References 53 publications

Supporting

Mentioning

181

Contrasting

Unclassified

Order By: Relevance

“…Another group recently identified a pre-B-cell population with concurrent expression of recombination activating genes and AID, providing additional support for the possibility that the t(c-MYC;Ig) translocation could occur early in development. 41 Biased, or stereotyped, usage of particular IGHV genes was observed in BL tumors, suggesting that BL progenitors carrying particular Ig genes preferentially differentiate into the memory B-cell compartment. Thus, BL progenitors are preferentially selected based on their BCR, and likely their antigenic specificity.…”

Section: Discussionmentioning

confidence: 99%

High-throughput sequencing of the B-cell receptor in African Burkitt lymphoma reveals clues to pathogenesis

et al. 2017

View full text Add to dashboard Cite

• High-throughput sequencing of primary African Burkitt lymphoma tumors suggests disrupted immunoglobulin rearrangements in BL progenitors.• Extensive mutation of expressed and nonexpressed IGH rearrangements suggests multiple active mutational processes in BL tumors. suggesting that the target of ongoing mutagenesis of these loci in BL tumor cells is not limited to expressed alleles. IGHV usage in both BL tumor cohorts revealed enrichment for IGHV genes that are infrequently used in memory B cells from healthy subjects. Analysis of publicly available DNA sequencing and RNAseq data revealed that these same IGHV genes were overrepresented in dominant tumor-associated IGH rearrangements in several independent BL tumor cohorts. These data suggest that BL derives from an abnormal B-cell progenitor and that aberrant mutational processes are active on the immunoglobulin loci in BL cells.

show abstract

Section: Discussionmentioning

confidence: 99%

High-throughput sequencing of the B-cell receptor in African Burkitt lymphoma reveals clues to pathogenesis

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Infection exposure was the first suggested cause for childhood ETV6-RUNX1 pB-ALL and remains one of the strongest candidates (3). Moreover, in vitro inflammatory and infection stimuli are known to increase RAG expression, which is relevant for the clonal evolution of human ETV6-RUNX1 pB-ALL (42)(43)(44). However, the role of infection in the conversion of the ETV6-RUNX1 preleukemic clone into pB-ALL remains unknown.…”

Section: Infection Exposure Induces Pb-all In Sca1-etv6-runx1 Micementioning

confidence: 99%

Infection Exposure PromotesETV6-RUNX1Precursor B-cell Leukemia via Impaired H3K4 Demethylases

et al. 2017

Self Cite

View full text Add to dashboard Cite

ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in timespace clusters keeps infection as a potential causal factor. Here, we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (KDM) family. KDM5C loss of function resulted in increased levels of H3K4me3, which coprecipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches.

show abstract

“…Although the majority of patients may be cured by the currently available therapeutic regimens, novel treatments are urgently required for the 20% of patients who experience relapse (1). The prevalence of BCP ALL may result, in part, from the fact that transformation generally occurs in cells arrested at the B-cell receptor checkpoint, a stage of differentiation associated with a balance between proliferation and recombination-activating gene-mediated DNA rearrangement (2)(3)(4). The stromal cytokine interleukin (IL)-7 serves an important role during this highly ordered process of differentiation, proliferation and somatic recombination (5-7).…”

Section: Introductionmentioning

confidence: 99%

Y-box-binding protein 1 contributes to IL-7-mediated survival signaling in B-cell precursor acute lymphoblastic leukemia

et al. 2016

View full text Add to dashboard Cite

Abstract. Y-box-binding protein 1 (YB-1) is a regulatory protein that is associated with drug resistance and relapse in solid tumors. As YB-1 mediates some of its activity through growth factor receptor signaling dysregulation, the present study compared the expression of YB-1 and interleukin 7 (IL-7) receptor α (IL-7Rα) in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) and normal BCP cells. The expression levels of IL-7Rα and YB-1 were higher in relapsed vs. diagnostic samples of primary BCP ALL; however, co-expression was also observed in a minor BCP cell population in samples from healthy donors. Functional crosstalk between YB-1 and IL-7R was detected: Overexpression of YB-1 increased surface levels of IL-7R in B cells, and the stimulation of BCP ALL cell lines and primary samples by IL-7 activated YB-1 by phosphorylation at S102 in a phosphatidylinositol 3-kinase-independent and MEK1/2-dependent manner. Targeted knockdown of YB-1 reduced IL-7-mediated protection against rapamycin, and an inhibitor of MEK1/2 potentiated rapamycin-mediated killing in the presence of IL-7. These data establish a novel link between two well-characterized pro-survival factors in acute leukemia, and suggest that YB-1 inhibition may represent a novel therapeutic strategy for increasing sensitivity to chemotherapy in patients with refractory acute B-cell leukemia.

show abstract

Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia

Cited by 180 publications

References 53 publications

High-throughput sequencing of the B-cell receptor in African Burkitt lymphoma reveals clues to pathogenesis

High-throughput sequencing of the B-cell receptor in African Burkitt lymphoma reveals clues to pathogenesis

Infection Exposure PromotesETV6-RUNX1Precursor B-cell Leukemia via Impaired H3K4 Demethylases

Y-box-binding protein 1 contributes to IL-7-mediated survival signaling in B-cell precursor acute lymphoblastic leukemia

Contact Info

Product

Resources

About