scholarly journals Protein kinase gene expression profiling and in vitro functional experiments identify novel potential therapeutic targets in adult acute lymphoblastic leukemia

Cancer ◽  
2010 ◽  
Vol 116 (14) ◽  
pp. 3426-3437 ◽  
Author(s):  
Monica Messina ◽  
Sabina Chiaretti ◽  
Simona Tavolaro ◽  
Nadia Peragine ◽  
Antonella Vitale ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Protein Kinase ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Lymphoblastic Leukemia ◽  
Kinase Gene ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Protein Kinase Gene

Gene Expression Profiling Data in Lymphoma and Leukemia: Review of the Literature and Extrapolation of Pertinent Clinical Applications

2006 ◽  
Vol 130 (4) ◽  
pp. 483-520 ◽  
Author(s):  
Cherie H. Dunphy
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Hodgkin Lymphoma ◽  
Expression Profiling ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Clinical Applications

Abstract Context.—Gene expression (GE) analyses using microarrays have become an important part of biomedical and clinical research in hematolymphoid malignancies. However, the methods are time-consuming and costly for routine clinical practice. Objectives.—To review the literature regarding GE data that may provide important information regarding pathogenesis and that may be extrapolated for use in diagnosing and prognosticating lymphomas and leukemias; to present GE findings in Hodgkin and non-Hodgkin lymphomas, acute leukemias, and chronic myeloid leukemia in detail; and to summarize the practical clinical applications in tables that are referenced throughout the text. Data Source.—PubMed was searched for pertinent literature from 1993 to 2005. Conclusions.—Gene expression profiling of lymphomas and leukemias aids in the diagnosis and prognostication of these diseases. The extrapolation of these findings to more timely, efficient, and cost-effective methods, such as flow cytometry and immunohistochemistry, results in better diagnostic tools to manage the diseases. Flow cytometric and immunohistochemical applications of the information gained from GE profiling assist in the management of chronic lymphocytic leukemia, other low-grade B-cell non-Hodgkin lymphomas and leukemias, diffuse large B-cell lymphoma, nodular lymphocyte–predominant Hodgkin lymphoma, and classic Hodgkin lymphoma. For practical clinical use, GE profiling of precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, and acute myeloid leukemia has supported most of the information that has been obtained by cytogenetic and molecular studies (except for the identification of FLT3 mutations for molecular analysis), but extrapolation of the analyses leaves much to be gained based on the GE profiling data.

scholarly journals High-Risk Subtype of Ph-like Acute Lymphoblastic Leukemia (ALL) in Adults: Dismal Outcomes of CRLF2+ ALL Patients Treated with Intensive Chemotherapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1082-1082 ◽  
Author(s):  
Nitin Jain ◽  
Kathryn G. Roberts ◽  
Elias J. Jabbour ◽  
Keyur Patel ◽  
Karina Eterovic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Hispanic Ethnicity ◽  
Oncology Research

Abstract Background:Ph-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of ALL in children. There are limited and conflicted data on the incidence and prognosis of Ph-like ALL in adults. Methods:Patients with newly-diagnosed B-ALL who received frontline chemotherapy at MD Anderson Cancer Center underwent gene expression profiling of leukemic cells to identify Ph-like ALL. Gene expression profiling was performed on 148 RNA samples using either U133 Plus 2.0 microarrays, or a customized Taqman low density array (LDA) card to identify patients with the Ph-like ALL gene signature (Roberts et al. NEJM 2014). An additional 7 previously untreated patients were found to have CRLF2 overexpression by multicolor flow-cytometry (MFC), and received induction chemotherapy at MDACC were included in the outcome analysis (but not for subtype frequency calculation). We performed targeted sequencing of 303 recurrently mutated genes (L300 panel, MDACC) in 40 patients with CRFL2 rearrangements (15 with matched germline control). Minimal residual disease (MRD) was assessed by MFC, with a sensitivity of 0.01%. Results:Of 148 patients, 49 (33.1%) were Ph-like, 46 patients (31.1%) were Ph+, and 53 patients (35.8%) were of other B-ALL subtypes (B-other). The median age of Ph-like cohort was 33.5 years (range, 15-71), Ph+ cohort was 49 years (range, 22-84), and B-other was 38 years (range, 15-79). Within the Ph-like ALL cohort, 61% had overexpression of CRLF2. Patients received hyper-CVAD (80%) or an augmented-BFM regimen (20%). The rate of CR/CRp was similar in the 3 disease subgroups (Ph-like ALL 89%, Ph+ ALL 93%, B-other 94%, p = 0.57). However, patients with Ph-like ALL were significantly less likely to achieve MRD-negative remission (30% vs. 56% for Ph+ ALL vs. 87% for B-other, p <0.001). Patients with Ph-like ALL had significantly worse overall survival (OS) and event-free survival (EFS) compared to B-other with a 5-year survival of 23% (vs. 59% for B-other, p=0.006) (Figure 1A). The poor outcomes of Ph-like ALL were also observed when only hyper-CVAD treated patients were considered. Interestingly, 68% of the patients with Ph-like ALL (78% among the CRLF2+ cohort) were of Hispanic ethnicity. This was significantly higher compared to Ph+ ALL (35%) and B-other (30%), p <0.001. Patients with CRLF2 overexpression had significantly inferior OS, EFS, and remission duration when compared to other genomic subgroups, including the Ph-like non-CRLF2 group (Figure 1B). Notably, 5-year survival in the CRLF2+ group was <20%. The following were independently associated with inferior OS on multivariable analysis: age (hazard ratio [HR] 2.474, p<0.001); WBC count (HR 1.183, p=0.007); platelet count (HR 4.283, p<0.001) and Ph-like ALL (HR 1.579, p=0.04) (Table 1). The most common mutations by L300 sequencing of 40 patients with CRLF2 were JAK2 (n=19, 47.5%), KRAS (n=10, 25%), CRLF2 (n=7, 17.5%), NRAS (n=5, 12.5%), PAX5 (n=5, 12.5%), JAK1 (n=4, 10%) (Figure 2). The CRLF2 F232C mutation, noted in 7 (17.5%) patients in this study, appears more frequent than in pediatric patients (3/134, 2.2%, Chen et al. Blood 2012), and in range with a smaller adult series (3/14, 21.4%, Yoda et al. PNAS 2010). CRLF2 F232C mutations were mutually exclusive with JAK2/JAK1 mutations (except in one patient). Conclusions:Our findings show a high frequency of Ph-like ALL in adults; an increased frequency of Ph-like ALL in adults with Hispanic ethnicity; significantly inferior outcomes of adult patients with Ph-like ALL; and significantly worse outcomes in Ph-like ALL patients with CRLF2 overexpression. The frequency of CRLF2 F232C mutation appears to be higher in adult patients with B-ALL than in the children. Ph-like ALL represents a high-risk disease subtype of adult B-ALL. Novel strategies are needed to improve the outcome of these patients. Disclosures Jain: Pharmacyclics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Incyte: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Infinity: Research Funding; Novimmune: Consultancy, Honoraria. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Mullighan:Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Loxo Oncology: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

scholarly journals Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome

Blood ◽  
2010 ◽  
Vol 116 (23) ◽  
pp. 4874-4884 ◽  
Author(s):  
Richard C. Harvey ◽  
Charles G. Mullighan ◽  
Xuefei Wang ◽  
Kevin K. Dobbin ◽  
George S. Davidson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Genome Wide

Abstract To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined poor-risk group with few known recurring cytogenetic abnormalities, we performed gene expression profiling in a cohort of 207 uniformly treated children with high-risk ALL. Expression profiles were correlated with genome-wide DNA copy number abnormalities and clinical and outcome features. Unsupervised clustering of gene expression profiling data revealed 8 unique cluster groups within these high-risk ALL patients, 2 of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and 6 of which lacked any previously known cytogenetic lesion. One unique cluster was characterized by high expression of distinct outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, and PTPRM; ERG DNA deletions; and 4-year relapse-free survival of 94.7% ± 5.1%, compared with 63.5% ± 3.7% for the cohort (P = .01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, and MUC4; frequent deletion of EBF1, IKZF1, RAG1-2, and IL3RA-CSF2RA; JAK mutations and CRLF2 rearrangements (P < .0001); and Hispanic ethnicity (P < .001) had a very poor 4-year relapse-free survival (21.0% ± 9.5%; P < .001). These studies reveal striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes that may serve as new targets for diagnosis, risk classification, and therapy.

Molecular Characterization of a Novel Subtype of Pediatric Acute Lymphoblastic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 482-482
Author(s):  
Charles G. Mullighan ◽  
Mary E. Ross ◽  
Xiaodong Zhou ◽  
James Dalton ◽  
Fred G. Behm ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Gene Expression Profiling ◽  
Gene Expression Profile ◽  
Expression Profiling ◽  
Lymphoblastic Leukemia ◽  
Gene Expression Signature ◽  
The Novel ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Genome Wide

Abstract Gene expression profiling is a powerful tool to classify and predict subtypes of pediatric acute lymphoblastic leukemia (ALL). In addition to accurately classifying known subtypes of ALL, microarray analysis of 327 cases of ALL at our institution using Affymetrix U95 arrays identified a previously uncharacterized novel subgroup of 14 cases of B-ALL with a gene expression signature distinct from other leukemias, suggesting a unique pathogenesis. These cases lacked a recurring cytogenetic anomaly, showed a high frequency of aberrant expression of CD2, lacked molecular markers of other subtypes of ALL, and had a favorable prognosis. We have used several complementary candidate and genome-wide approaches to identify the molecular basis of this novel subtype. Gene expression profiling using Affymetrix U133A and B arrays was used to refine the signature, and when applied to an additional 36 cases of cytogenetically normal B-ALL, 5 cases were identified that share the novel gene expression profile. Intriguingly, the tyrosine kinase PDGFRA was overexpressed in the majority of the novel cases, with 6 novel cases showing exceedingly high levels of PDGFRA expression, which was confirmed by western blotting and flow cytometry. Unexpectedly, 3 of these cases harbored the FIP1L1-PDGFRA fusion characteristic of idiopathic hypereosinophilic syndrome. However, FISH examination demonstrated that this fusion was present in a minor subclone only. RT-PCR and FISH approaches failed to identify alternative PDGFRA fusions, and PDGFRA sequencing failed to identify evidence of activating mutations. Furthermore, in unstimulated cultures or following PDGF-AA stimulation, PDGFRA-overexpressing ALL blasts were not sensitive to imatinib (Gleevec). Other genes in the gene expression profile with potential roles in leukemogenesis, include include the B-cell receptor signaling mediator BRDG1 and the tyrosine phosphatase PTPRM. Using FISH and genomic sequencing of multiple candidates, no potentially leukemogenic abnormality has been identified. To determine if gene amplification, deletion, or copy-neutral loss of heterozygosity is characteristic of this subtype of ALL, genome-wide array-based comparative genomic hybridization and Affymetrix 100K single nucleotide polymorphism arrays were performed on all cases. Deletion of the CDKN2A/2B locus, and deletion of a region at 8p22–23.1 flanking the SPAG11 locus were each found in multiple cases, however no single unifying abnormality was identified. In summary, we have identified and characterized a novel subtype of B-ALL with unique gene expression signature, high incidence of CD2 and PDGFRA overexpression, and favorable outcome. Although no uniform causal molecular lesion has been identified, FIP1L1-PDGFRA fusion may represent one mechanism of PDGFRA overexpression. Further studies and analysis of additional cases may prove informative.

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