Genomic Profiling of T-Cell Neoplasms Reveals Frequent <i>JAK1</i> and <i>JAK3</i> Mutations With Clonal Evasion From Targeted Therapies

Greenplate, Allison R.; Wang, Kai; Tripathi, Rati; Palma, Norma Alonzo; Ali, Siraj M.; Stephens, Phil; Miller, Vincent A.; Shyr, Yu; Guo, Yan; Reddy, Nishitha; Kozhaya, Lina; Unutmaz, Derya; Chen, Xueyan; Irish, Jonathan M.; Davé, Utpal P.

doi:10.1200/po.17.00019

Cited by 28 publications

(27 citation statements)

References 53 publications

(48 reference statements)

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“…Germline controls were sequenced in 53 cases (19.3%). The number of analyzed patients varied from 3 to 71 patients across the 10 studies [9][10][11][12][13][14][15][16][17][18]. After subtracting all cases reported in more than one study, we identified 275 unique T-PLL cases as the core cohort.…”

Section: Characteristics and Overlaps Of Included Studiesmentioning

confidence: 99%

“…[14][15][16][17][18][19][20], JAK3 (Ex. [11][12][13][14][15][16][17][18][19], and/or STAT5B (Ex. [15][16][17], was included.…”

Section: Characteristics and Overlaps Of Included Studiesmentioning

confidence: 99%

“…[11][12][13][14][15][16][17][18][19], and/or STAT5B (Ex. [15][16][17], was included. (D) Box-whisker charted allele frequencies of missense mutations of JAK1, JAK3, and STAT5B (n = 153 T-PLL analyzed by WGS/WES and/or TAS) illustrate a high heterogeneity in variant allele fractions, with most lesions detected at lower frequencies (<50%).…”

Section: Characteristics and Overlaps Of Included Studiesmentioning

confidence: 99%

“…The second most common lesions are genomic alterations of the tumor suppressor ataxia telangiectasia mutated (ATM), found in >85% of cases [9]. In addition to these lesions, activating mutations targeting the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway components were identified in these series of genomic analyses [9][10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

“…Constitutively active JAK/STAT signaling induces T-cell tumors in mice [22,23]. Using different sequencing approaches, activating mutations of JAK1, JAK3, and STAT5B were identified as the most recurrent genomic aberrations affecting JAK/STAT genes in T-PLL [9][10][11][12][13][14][15][16][17][18]. However, prevalence of gene mutations, information on their allele frequencies, assessment of negative regulators of JAK/STAT signaling, and the phosphorylation status of the most recurrently affected JAK/STAT proteins vary considerably or are not reported in these studies [9][10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL

Wahnschaffe

Braun

Timonen

et al. 2019

Cancers

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T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell leukemia. Recent studies detected genomic aberrations affecting JAK and STAT genes in T-PLL. Due to the limited number of primary patient samples available, genomic analyses of the JAK/STAT pathway have been performed in rather small cohorts. Therefore, we conducted-via a primary-data based pipeline-a meta-analysis that re-evaluated the genomic landscape of T-PLL. It included all available data sets with sequence information on JAK or STAT gene loci in 275 T-PLL. We eliminated overlapping cases and determined a cumulative rate of 62.1% of cases with mutated JAK or STAT genes. Most frequently, JAK1 (6.3%), JAK3 (36.4%), and STAT5B (18.8%) carried somatic single-nucleotide variants (SNVs), with missense mutations in the SH2 or pseudokinase domains as most prevalent. Importantly, these lesions were predominantly subclonal. We did not detect any strong association between mutations of a JAK or STAT gene with clinical characteristics. Irrespective of the presence of gain-of-function (GOF) SNVs, basal phosphorylation of STAT5B was elevated in all analyzed T-PLL. Fittingly, a significant proportion of genes encoding for potential negative regulators of STAT5B showed genomic losses (in 71.4% of T-PLL in total, in 68.4% of T-PLL without any JAK or STAT mutations). They included DUSP4, CD45, TCPTP, SHP1, SOCS1, SOCS3, and HDAC9.Overall, considering such losses of negative regulators and the GOF mutations in JAK and STAT genes, a total of 89.8% of T-PLL revealed a genomic aberration potentially explaining enhanced STAT5B activity. In essence, we present a comprehensive meta-analysis on the highly prevalent genomic lesions that affect genes encoding JAK/STAT signaling components. This provides an overview of possible modes of activation of this pathway in a large cohort of T-PLL. In light of new advances in JAK/STAT inhibitor development, we also outline translational contexts for harnessing active JAK/STAT signaling, which has emerged as a 'secondary' hallmark of T-PLL.

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