Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells

dc.contributorUniversidade Estadual Paulista (UNESP)
dc.creatorReichel, Jonathan
dc.creatorChadburn, Amy
dc.creatorRubinstein, Paul G.
dc.creatorGiulino-Roth, Lisa
dc.creatorTam, Wayne
dc.creatorLiu, Yifang
dc.creatorGaiolla, Rafael
dc.creatorEng, Kenneth
dc.creatorBrody, Joshua
dc.creatorInghirami, Giorgio
dc.creatorCarlo-Stella, Carmelo
dc.creatorSantoro, Armando
dc.creatorRahal, Daoud
dc.creatorTotonchy, Jennifer
dc.creatorElemento, Olivier
dc.creatorCesarman, Ethel
dc.creatorRoshal, Mikhail
dc.date2015-10-21T13:08:51Z
dc.date2016-10-25T20:59:17Z
dc.date2015-10-21T13:08:51Z
dc.date2016-10-25T20:59:17Z
dc.date2015-02-12
dc.date.accessioned2017-04-06T08:57:10Z
dc.date.available2017-04-06T08:57:10Z
dc.identifierBlood. Washington: Amer Soc Hematology, v. 125, n. 7, p. 1061-1072, 2015.
dc.identifier0006-4971
dc.identifierhttp://hdl.handle.net/11449/128305
dc.identifierhttp://acervodigital.unesp.br/handle/11449/128305
dc.identifierhttp://dx.doi.org/10.1182/blood-2014-11-610436
dc.identifierWOS:000350818800007
dc.identifierhttp://www.bloodjournal.org/content/125/7/1061?sso-checked=true
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/938861
dc.descriptionClassical Hodgkin lymphoma (cHL) is characterized by sparsely distributed Hodgkin and Reed-Sternberg (HRS) cells amid reactive host background, complicating the acquisition of neoplastic DNA without extensive background contamination. We overcame this limitation by using flow-sorted HRS and intratumor T cells and optimized low-input exome sequencing of 10 patient samples to reveal alterations in genes involved in antigen presentation, chromosome integrity, transcriptional regulation, and ubiquitination. beta-2-microglobulin (B2M) is the most commonly altered gene in HRS cells, with 7 of 10 cases having inactivating mutations that lead to loss of major histocompatibility complex class I (MHC-I) expression. Enforced wild-type B2M expression in a cHL cell line restored MHC-I expression. In an extended cohort of 145 patients, the absence of B2M protein in the HRS cells was associated with lower stage of disease, younger age at diagnosis, and better overall and progression-free survival. B2M-deficient cases encompassed most of the nodular sclerosis subtype cases and only a minority of mixed cellularity cases, suggesting that B2M deficiency determines the tumor microenvironment and may define a major subset of cHL that has more uniform clinical and morphologic features. In addition, we report previously unknown genetic alterations that may render selected patients sensitive to specific targeted therapies.
dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.languageeng
dc.publisherAmer Soc Hematology
dc.relationBlood
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.titleFlow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells
dc.typeOtro


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