Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation

Lane, Andrew A.; Chapuy, Bjoern; Lin, Charles Y.; Tivey, Trevor; Li, Hubo; Townsend, Elizabeth; Bodegom, Diederik van; Day, Tovah; Wu, Shuo; Liu, Huiyun; Yoda, Akinori; Alexe, Gabriela; Schinzel, Anna C.; Sullivan, Timothy J.; Malinge, Sébastien; Taylor, Jordan E.; Stegmaier, Kimberly; Jaffe, Jacob D.; Bustin, Michael; Kronnie, Geertruy te; Izraeli, Shai; Harris, Marian H.; Stevenson, Kristen E.; Neuberg, Donna; Silverman, Lewis B.; Sallan, Stephen E.; Bradner, James E.; Hahn, William C.; Crispino, John D.; Pellman, David; Weinstock, David M.

doi:10.1038/ng.2949

Cited by 122 publications

(142 citation statements)

References 58 publications

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“…To test this hypothesis, the fi rst group was composed of Pax5 +/− mice and control littermate wild-type (WT) mice born and kept in a specifi c pathogen-free (SPF) environment during their lifespan. These Pax5 +/− mice did not spontaneously develop pB-ALL after 2 years, corroborating previous results ( 16,17 ). The second group was composed of Pax5 +/− mice and control littermate WT mice born and kept in the SPF environment until moved to a common infectious environment ( Fig.…”

Section: Introductionsupporting

confidence: 75%

Infection Exposure Is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result ofPax5-Inherited Susceptibility

et al. 2015

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Earlier in the past century, infections were regarded as the most likely cause of childhood B-cell precursor acute lymphoblastic leukemia (pB-ALL). However, there is a lack of relevant biologic evidence supporting this hypothesis. We present in vivo genetic evidence mechanistically connecting inherited susceptibility to pB-ALL and postnatal infections by showing that pB-ALL was initiated in Pax5 heterozygous mice only when they were exposed to common pathogens. Strikingly, these murine pB-ALLs closely resemble the human disease. Tumor exome sequencing revealed activating somatic, nonsynonymous mutations of Jak3 as a second hit. Transplantation experiments and deep sequencing suggest that inactivating mutations in Pax5 promote leukemogenesis by creating an aberrant progenitor compartment that is susceptible to malignant transformation through accumulation of secondary Jak3 mutations. Thus, treatment of Pax5 +/− leukemic cells with specifi c JAK1/3 inhibitors resulted in increased apoptosis. These results uncover the causal role of infection in pB-ALL development.SIGNIFICANCE: These results demonstrate that delayed infection exposure is a causal factor in pB-ALL. Therefore, these fi ndings have critical implications for the understanding of the pathogenesis of leukemia and for the development of novel therapies for this disease. Cancer Discov; 5(12); 1328-43.

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Section: Introductionsupporting

confidence: 75%

Infection Exposure Is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result ofPax5-Inherited Susceptibility

et al. 2015

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“…Defects specific to certain aneuploidies as well as defects observed in all aneuploid strains analyzed were evident in our aneuploid HSCs. The lineage-specific defects such as reduced B-cell number observed in trisomy 16 FL-HSC reconstitutions are likely due to chromosome-specific effects, as B-cell differentiation defects have also been observed in DS (Roy et al 2012;Lane et al 2014). Furthermore, we observed decreased proliferative potential in all aneuploidy models that we examined.…”

Section: The Effects Of Aneuploidy and Cin On Hsc Fitness And Hematopmentioning

confidence: 50%

Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

et al. 2016

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Aneuploidy, an imbalanced karyotype, is a widely observed feature of cancer cells that has long been hypothesized to promote tumorigenesis. Here we evaluate the fitness of cells with constitutional trisomy or chromosomal instability (CIN) in vivo using hematopoietic reconstitution experiments. We did not observe cancer but instead found that aneuploid hematopoietic stem cells (HSCs) exhibit decreased fitness. This reduced fitness is due at least in part to the decreased proliferative potential of aneuploid hematopoietic cells. Analyses of mice with CIN caused by a hypomorphic mutation in the gene Bub1b further support the finding that aneuploidy impairs cell proliferation in vivo. Whereas nonregenerating adult tissues are highly aneuploid in these mice, HSCs and other regenerative adult tissues are largely euploid. These findings indicate that, in vivo, mechanisms exist to select against aneuploid cells.

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“…13 It was recently shown that trisomy 21 leads to overexpression of HMGN1, which may promote B-lineage ALL by suppressing trimethylation of lysine 27 of histone H3. 14 The risk of all major groups of malignant solid tumors was decreased with the exception of testicular cancer. The risk of solid tumors was significantly reduced for men and women over 40 years of age; among the oldest age groups the cancer incidence was only 25% of that seen in the general population.…”

Section: Discussionmentioning

confidence: 99%

Low risk of solid tumors in persons with Down syndrome

Hasle

Friedman

Olsen

et al. 2016

Genetics in Medicine

150

139

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Purpose: The aim of this study was to investigate cancer incidence in a large cohort of persons with Down syndrome.Methods: Down syndrome was identified from the Danish Cytogenetic Register. Cancer occurrence was identified by linkage to the Danish Cancer Registry. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated based on observed and expected numbers from rates for all Danish residents. The cohort consisted of 3,530 persons with Down syndrome contributing 89,570 person-years at risk.Results: Acute leukemia risk was highest from 1-4 years of age and remained elevated until age 30. The overall risk of solid tumors was decreased (SIR 0.45; 95% CI 0.34-0.59), especially in persons 50 years or older (SIR 0.27; 95% CI 0.16-0.43). We found a significantly lower risk of lung cancer (SIR 0.10; 95% CI 0.00-0.56), breast cancer (SIR 0.16; 95% CI 0.03-0.47), and cervical cancer (SIR 0.0; 95% CI 0.00-0.77). Testicular cancer was the only solid tumor with an increased SIR (2.9; 95% CI 1.6-4.8). Conclusions:The risk of all major groups of solid tumors was decreased, except testicular cancer. Altered screening strategies should be considered for persons with Down syndrome. This unusual pattern of cancer occurrence may help understanding carcinogenesis in the general population.

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Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation

Cited by 122 publications

References 58 publications

Infection Exposure Is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result ofPax5-Inherited Susceptibility

Infection Exposure Is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result ofPax5-Inherited Susceptibility

Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

Low risk of solid tumors in persons with Down syndrome

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