Ph-like acute lymphoblastic leukemia in adults is characterized by IgH-CRFL2 and JAK2 mutations and poor prognosis
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PROVIDER: PRJNA276456 | ENA |
REPOSITORIES: ENA
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Project description:Philadelphia-like B-cell precursor acute lymphoblastic leukemia (Ph-like ALL) is characterized by distinct genetic alterations and inferior prognosis in children and younger adults. The purpose of this study was the genetic and clinical characterization of Ph-like ALL in adults. Among 207 adult B-cell precursor ALL patients, 26 (13%) were classified as Ph-like using Affymetrix microarrays. The incidence of this subtype was 25% among 105 B-cell precursor ALL patients negative for BCR-ABL1 and MLL-translocations (B-other). All patients with IgH-CRLF2 translocation (38% vs 0%; p=0.002) or mutations in JAK2 (44% vs. 0%; p<0.001) were exclusively found in the Ph-like subgroup. Clinical and outcome analyses were restricted to patients treated within GMALL trials 06/99 and 07/03 (n=107). The complete remission (CR) rate after induction was 100% for Ph-like (n=19) and B-other patients (n=40). After induction, significantly fewer Ph-like patients reached molecular CR (33% vs 79%; p=0.01). At 5 years, the Ph-like ALL subgroup had a lower probability of continuous CR (24% vs 62%; p<0.001) and overall survival (22% vs 64%; p=0.006) compared to B-other ALL patients. Subsequent analysis led to a clinically applicable algorithm identifying this patient subset with a specificity of 100%. Our study is the first to demonstrate that the profile of genetic events in adult Ph-like ALL resembles pediatric Ph-like ALL and differs from B-other ALL. The Ph-like phenotype associates with inferior outcomes in intensively treated adult ALL patients. Ph-like adult ALL should be recognized as a distinct, high-risk entity and further research on improved diagnostic and therapeutic approaches is needed.
2017-02-28 | GSE66005 | GEO
Project description:Philadelphia-like B-cell precursor acute lymphoblastic leukemia (Ph-like ALL) is characterized by distinct genetic alterations and inferior prognosis in children and younger adults. The purpose of this study was the genetic and clinical characterization of Ph-like ALL in adults. Among 207 adult B-cell precursor ALL patients, 26 (13%) were classified as Ph-like using Affymetrix microarrays. The incidence of this subtype was 25% among 105 B-cell precursor ALL patients negative for BCR-ABL1 and MLL-translocations (B-other). All patients with IgH-CRLF2 translocation (38% vs 0%; p=0.002) or mutations in JAK2 (44% vs. 0%; p<0.001) were exclusively found in the Ph-like subgroup. Clinical and outcome analyses were restricted to patients treated within GMALL trials 06/99 and 07/03 (n=107). The complete remission (CR) rate after induction was 100% for Ph-like (n=19) and B-other patients (n=40). After induction, significantly fewer Ph-like patients reached molecular CR (33% vs 79%; p=0.01). At 5 years, the Ph-like ALL subgroup had a lower probability of continuous CR (24% vs 62%; p<0.001) and overall survival (22% vs 64%; p=0.006) compared to B-other ALL patients. Subsequent analysis led to a clinically applicable algorithm identifying this patient subset with a specificity of 100%. Our study is the first to demonstrate that the profile of genetic events in adult Ph-like ALL resembles pediatric Ph-like ALL and differs from B-other ALL. The Ph-like phenotype associates with inferior outcomes in intensively treated adult ALL patients. Ph-like adult ALL should be recognized as a distinct, high-risk entity and further research on improved diagnostic and therapeutic approaches is needed.
2017-02-28 | GSE66004 | GEO
Project description:Philadelphia-like B-cell precursor acute lymphoblastic leukemia (Ph-like ALL) is characterized by distinct genetic alterations and inferior prognosis in children and younger adults. The purpose of this study was the genetic and clinical characterization of Ph-like ALL in adults. Among 207 adult B-cell precursor ALL patients, 26 (13%) were classified as Ph-like using Affymetrix microarrays. The incidence of this subtype was 25% among 105 B-cell precursor ALL patients negative for BCR-ABL1 and MLL-translocations (B-other). All patients with IgH-CRLF2 translocation (38% vs 0%; p=0.002) or mutations in JAK2 (44% vs. 0%; p<0.001) were exclusively found in the Ph-like subgroup. Clinical and outcome analyses were restricted to patients treated within GMALL trials 06/99 and 07/03 (n=107). The complete remission (CR) rate after induction was 100% for Ph-like (n=19) and B-other patients (n=40). After induction, significantly fewer Ph-like patients reached molecular CR (33% vs 79%; p=0.01). At 5 years, the Ph-like ALL subgroup had a lower probability of continuous CR (24% vs 62%; p<0.001) and overall survival (22% vs 64%; p=0.006) compared to B-other ALL patients. Subsequent analysis led to a clinically applicable algorithm identifying this patient subset with a specificity of 100%. Our study is the first to demonstrate that the profile of genetic events in adult Ph-like ALL resembles pediatric Ph-like ALL and differs from B-other ALL. The Ph-like phenotype associates with inferior outcomes in intensively treated adult ALL patients. Ph-like adult ALL should be recognized as a distinct, high-risk entity and further research on improved diagnostic and therapeutic approaches is needed.
2017-02-28 | GSE66002 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-02-28 | GSE66006 | GEO
Project description:Philadelphia-like B-cell precursor acute lymphoblastic leukemia (Ph-like ALL) is characterized by distinct genetic alterations and inferior prognosis in children and younger adults. The purpose of this study was a genetic and clinical characterization of Ph-like ALL in adults. Twenty-six (13%) of 207 adult patients (median age: 42 years) with B-cell precursor ALL (BCP-ALL) were classified as having Ph-like ALL using gene expression profiling. The frequency of Ph-like ALL was 27% among 95 BCP-ALL patients negative for BCR-ABL1 and KMT2A-rearrangements. IGH-CRLF2 rearrangements (6/16; P=0.002) and mutations in JAK2 (7/16; P<0.001) were found exclusively in the Ph-like ALL subgroup. Clinical and outcome analyses were restricted to patients treated in German Multicenter Study Group for Adult ALL (GMALL) trials 06/99 and 07/03 (n=107). The complete remission rate was 100% among both Ph-like ALL patients (n=19) and the "remaining BCP-ALL" cases (n=40), i.e. patients negative for BCR-ABL1 and KMT2A-rearrangements and the Ph-like subtype. Significantly fewer Ph-like ALL patients reached molecular complete remission (33% versus 79%; P=0.02) and had a lower probability of continuous complete remission (26% versus 60%; P=0.03) and overall survival (22% versus 64%; P=0.006) at 5 years compared to the remaining BCP-ALL patients. The profile of genetic lesions in adults with Ph-like ALL, including older adults, resembles that of pediatric Ph-like ALL and differs from the profile in the remaining BCP-ALL. Our study is the first to demonstrate that Ph-like ALL is associated with inferior outcomes in intensively treated older adult patients. Ph-like adult ALL should be recognized as a distinct, high-risk entity and further research on improved diagnostic and therapeutic approaches is needed. (NCT00199056, NCT00198991).
| S-EPMC5210243 | biostudies-literature
Project description:Over 80% of patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP achieve complete remission with variable 5-year overall survival (OS) rates of 60 to 70% depending on the preexisting risk factors. We herein attempted to stratify DLBCL by the patterns of immunoglobulin heavy chain gene rearrangement (IgH-R) by using a PCR-based clonality detection method to predict prognosis of the patients with DLBCL. We retrospectively analyzed 81 patients with DLBCL who were treated at our hospital from 2006 to 2013 and had data on IgH-R of lymphoma cells at diagnosis. IgH-R analyses identified a uniform pattern of IgH-R harboring all frame regions (FR)1-3 not completely involving DH1-7 in 15 out of 26 patients, who failed to obtain complete remission (CR). Moreover, CR rate was quite low ((7/22 (32%)) in these patients with this IgH-R pattern. We evaluated prognostic parameters of these patients with special reference to patterns of IgH-R by univariate and multivariate proportional-hazard model. Multivariate analysis revealed that IgH-R in all FR1-3 without entire DH1-7 was significantly associated with adverse overall survival. Then, gene expression profiling of mRNA elicited the candidate genes associated with poorer prognosis stratified by IgH-R patterns. Among them, CDC25A mRNA was significantly amplified by real-time PCR and then further analysis of its protein with immunostaining confirmed that CDC25A could be a responsible gene for prognosis of patients with DLBCL. These results may shed light on individualized therapeutic modalities by the stratification of patients in accordance with patterns of IgH-R.
2018-02-24 | GSE111069 | GEO
Project description:TEL-JAK2 is a fusion oncogene resulting from a t(9;12) chromosomal translocation in T-ALL, translated as a constitutively activated TEL-JAK2 tyrosine kinase. Mice carrying a TEL-JAK2 transgene develop T-ALL. Gene deregulated in TEL-JAK2 T-ALL cells as compared to mouse thymocytes were identified Leukemic cells were collected from the thymus of terminally-ill TEL-JAK2 mice; thymocytes were collected from the thymus of 2 months-old mice. All mice on C57B/6 background. RNA was extracted from each sample and processed for hybridization to Affymetrix arrays.
2013-09-28 | E-GEOD-51241 | biostudies-arrayexpress
Project description:TEL-JAK2 is a fusion oncogene resulting from a t(9;12) chromosomal translocation in T-ALL, translated as a constitutively activated TEL-JAK2 tyrosine kinase. Mice carrying a TEL-JAK2 transgene develop T-ALL. Gene deregulated in TEL-JAK2 T-ALL cells as compared to mouse thymocytes were identified
2013-09-28 | GSE51241 | GEO
Project description:SPAG9-JAK2 is a novel fusion gene identified in a pediatric patient with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). In this study, we performed functional analysis of the SPAG9-JAK2 fusion to establish molecular targeted therapy. Ba/F3 cells expressing SPAG9-JAK2 generated by retroviral transduction (Ba/F3-SPAG9-JAK2), proliferated in the absence of IL-3, and exhibited constitutive phosphorylation of the tyrosine residues in the JAK2 kinase domain of the fusion protein and STAT3/STAT5. Mutation of tyrosine residues in the JAK2 kinase domain (SPAG9-JAK2 mut) abolished IL-3 independence, but had no influence on STAT3/STAT5 phosphorylation levels. Gene expression analysis revealed that Stat1 was significantly up-regulated in Ba/F3-SPAG9-JAK2 cells. STAT1 was also phosphorylated in Ba/F3-SPAG9-JAK2 but not SPAG9-JAK2 mut cells, suggesting that STAT1 is key for SPAG9-JAK2-mediated cell proliferation. Consistently, STAT1 induced expression of the anti-apoptotic proteins, BCL-2 and MCL-1, as did SPAG9-JAK2, but not SPAG9-JAK2 mut. Ruxolitinib abrogated Ba/F3-SPAG9-JAK2-mediated proliferation in vitro, but was insufficient in vivo. Venetoclax (a BCL-2 inhibitor) or AZD5991 (an MCL-1 inhibitor) enhanced the effects of ruxolitinib on Ba/F3-SPAG9-JAK2 in vitro. These findings suggest that activation of the JAK2-STAT1-BCL-2/MCL-1 axis contributes to SPAG9-JAK2-related aberrant growth promotion. BCL-2 or MCL-1 inhibition is a potential therapeutic option for B-ALL with SPAG9-JAK2 fusion.
2021-05-18 | GSE174578 | GEO
Project description:PAX5-JAK2 has recently been identified as a novel recurrent fusion gene in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) but the function of the encoded chimeric protein has not yet been characterized in detail. Herein we show that the PAX5-JAK2 chimera, which consists of the DNA-binding paired domain of PAX5 and the active kinase domain of JAK2, is a nuclear protein that has the ability to bind to wild-type PAX5 target loci. Moreover, our data provide compelling evidence that PAX5-JAK2 functions as nuclear catalytically active kinase that autophosphorylates and in turn phosphorylates and activates downstream STATs in an apparently non-canonical mode. The chimeric protein also enables cytokine-independent growth of Ba/F3 cells and, therefore, possessing transforming potential. Importantly, the kinase activity of PAX5-JAK2 can be efficiently blocked by JAK2 inhibitors rendering it a potential target for therapeutic intervention. Together, our data show that PAX5-JAK2 simultaneously deregulates the PAX5 downstream transcriptional program and activates the JAK-STAT signaling cascade, and thus, by interfering with these two important pathways, may promote leukemogenesis.
2014-12-29 | GSE56449 | GEO