Transient Response to Imatinib in an Atypical Chronic Myeloproliferative Disease Associated with ins(9;4)(q34;q21q31) and a CDK5RAP2-PDGFRA Fusion Gene.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3281-3281
Author(s):  
Christoph Walz ◽  
Beate Schultheis ◽  
Georgia Metzgeroth ◽  
Claudia Schoch ◽  
Claire Curtis ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Fusion Gene ◽  
Regulatory Subunit ◽  
Fish Analysis ◽  
Myeloproliferative Disease ◽  
Rt Pcr ◽  
Molecular Remission ◽  
Advanced Phase

Abstract Chronic myeloproliferative disorders (CMPD) associated with rearrangements of the ‘platelet-derived growth factor receptor A’ (PDGFRA) at chromosome 4q12 are excellent candidates for targeted therapy with imatinib. To date, two fusion genes involving PDGFRA have been described: FIP1L1-PDGFRA and BCR-PDGFRA. Here we report a female patient who presented in advanced phase of an atypical myeloproliferative disease. Routine cytogenetic analysis revealed an ins(9;4)(q34;q21q31). Although no break was visible at 4q12, FISH analysis with flanking BAC probes indicated that PDGFRA was disrupted. To identify the partner gene we employed 5′-RACE PCR, exploiting the fact that all known PDGFRA fusions involve exon 12 of this gene. The resulting PCR-products consisted of 5′-sequences derived from CDK5RAP2 (CDK5 regulatory subunit associated protein 2) located on 9q33 and 3′-sequences derived from PDGFRA. CDK5RAP2 encodes a protein that is believed to be involved in centrosomal regulation. FISH analysis confirmed the co-localization of 5′ CDK5RAP2 and 3′ PDGFRA sequences. RT-PCR confirmed the in-frame mRNA fusion between exon 13 of CDK5RAP2, a 40-bp insert which was partially derived from PDGFRA intron 11 and a truncated PDGFRA exon 12. No reciprocal fusion transcript could be amplified by RT-PCR. The predicted CDK5RAP2-PDGFRA protein consists of 1003 amino acids and retains both tyrosine kinase domains of PDGFRA and several potential dimerisation domains of CDK5RAP2 suggesting a mechanism of tyrosine kinase activation similar to BCR-ABL. Treatment with 400 mg imatinib was initiated and the patient achieved a complete cytogenetic and molecular remission. However, hematological response was only partial with residual blasts repeatedly detectable in the blood and marrow. The patient rapidly developed acute leukemia while still remaining in complete cytogenetic and molecular remission suggesting the outgrowth of a second imatinib-resistant leukemic clone. These findings and the fact that the ins(9;4) was only seen in 24% of metaphases at diagnosis suggests that CDK5RAP2-PDGFRA may have been a secondary abnormality. In summary, we have identified a third fusion gene involving PDGFRA, underlining the fundamental role of activated tyrosine kinases in CMPD’s and their possible response to targeted therapy with imatinib.

Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor β receptor fusion oncogene

Blood ◽  
2002 ◽  
Vol 100 (3) ◽  
pp. 1088-1091 ◽  
Author(s):  
Magnus K. Magnusson ◽  
Kristin E. Meade ◽  
Ryotaro Nakamura ◽  
John Barrett ◽  
Cynthia E. Dunbar
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Chronic Myelomonocytic Leukemia ◽  
Platelet Derived Growth Factor ◽  
Gene Transcript ◽  
Molecular Remission ◽  
Β Receptor ◽  
Myelomonocytic Leukemia

Abstract Platelet-derived growth factor β receptor (PDGFβR) fusion genes have been shown to be critical transforming oncogenes in a subset of patients with chronic myelomonocytic leukemia (CMML). The sensitivity of dysregulated tyrosine kinase oncogenes to the tyrosine kinase inhibitor STI571 (imatinib mesylate) makes it a potentially attractive treatment option in this subset of patients. We have recently cloned a novel member of the PDGFβR fusion oncogene family, rabaptin-5-PDGFβR. A patient with CMML carrying the rabaptin-5-PDGFβR fusion gene underwent allogeneic stem cell transplantation (SCT) and was monitored closely with a sensitive reverse transcriptase–polymerase chain assay to detect the novel fusion gene transcript. After achieving a molecular remission at 5 months after transplantation, 15 months after SCT the patient showed persistent and progressive evidence of molecular relapse. After demonstrating in vitro that cells transformed with this specific fusion oncogene are efficiently killed by STI571, the patient was started on STI571. The patient responded rapidly and entered molecular remission after 6 weeks of therapy, and he continues to be in remission 6 months later. These results suggest that STI571 may be an effective targeted therapy in patients with CMML related to PDGFβR fusion oncogenes.

Fusion of SFQP to ABL in a Patient with a T(1;9)(p34;q34) and Acute Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4444-4444
Author(s):  
Nicholas C.P. Cross ◽  
Andrew J. Chase ◽  
Milton Drachenberg ◽  
W. Mark Roberts ◽  
Jerry Z. Finklestein ◽  
...  
Keyword(s):  
Complete Remission ◽  
Fusion Gene ◽  
Chimeric Protein ◽  
Sh2 Domain ◽  
Lymphocytic Leukemia ◽  
Tyrosine Kinase Domain ◽  
Fish Analysis ◽  
Fusion Partner ◽  
Rt Pcr ◽  
Polypyrimidine Tract Binding Protein

Abstract We have investigated a child who presented with pre-B ALL and an acquired t(1;9)(p34;q34). BCR-ABL was not detected by RT-PCR or FISH analysis, however FISH did indicate that the ABL gene at 9q34 was disrupted. To identify the putative partner locus in this case, a modified 5′RACE strategy was employed that selected against normal ABL transcripts. Several clones were recovered in which ABL was fused to SFPQ (also known as PSF), a gene mapping to 1p34 that encodes a polypyrimidine tract-binding protein-associated splicing previously identified as a fusion partner of the helix-loop-helix transcription factor TFE3 in papillary renal cell carcinomas. Both SFPQ-ABL and reciprocal ABL-SFPQ transcripts were detectable by RT-PCR, and disruption of these two genes was further confirmed by amplification and sequencing of the forward genomic breakpoint. SFPQ-ABL, the likely oncogenic product, is predicted to encode a protein that retains the coiled coil domain of SFPQ and the entire tyrosine kinase domain and C-terminal sequences of ABL. The breakpoint in ABL was downstream of that seen for other ABL fusion genes and the chimeric protein is predicted to lack the ABL-encoded SH3 domain and part of the SH2 domain. The patient was treated according to the Children’s Cancer Group Protocol 1961 and subsequently received augmented BFM therapy with doxorubicin and double delayed intensification. He achieved complete remission but suffered extramedullary testicular relapse at 4.5 years. Following orchiectomy and intensive chemotherapy he remains in complete remission more than 6 years after diagnosis. We conclude that SFPQ-ABL is a novel fusion gene associated with ALL. Although the patient here responded to conventional chemotherapy, SFPQ-ABL is likely to be sensitive to imatinib and use of this agent might be considered in further cases.

Two Distinct Subsets of dic(9;12)(p12;p11.2) among Children with B-Cell Precursor Acute Lymphoblastic Leukemia (ALL): PAX5-ETV6 and ETV6-RUNX1 Rearrangements: A Report from the Children’s Oncology Group.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1439-1439 ◽  
Author(s):  
Julie M. Gastier-Foster ◽  
Andrew J. Carroll ◽  
Denise Ell ◽  
Richard Harvey ◽  
I-Ming Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Gene Rearrangement ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Cytogenetic Abnormality ◽  
Fish Analysis ◽  
Oncology Group ◽  
Rt Pcr ◽  
Cell Precursor ◽  
Pediatric All

Abstract The dic(9;12)(p12;p11.2) has been described as a rare cytogenetic abnormality in pediatric precursor B-cell ALL. Initial studies suggested that the rearrangement is associated with a favorable outcome, and recent studies demonstrated the presence of a PAX5-ETV6 fusion gene was associated with this cytogenetic abnormality. Twenty cases with a cytogenetic dic(9;12) were identified in the Children’s Oncology Group (COG) cytogenetics databases. FISH analysis with the ETV6-RUNX1 (TEL-AML1) probes was done on 12 of these samples. Five cases were positive for fusion, indicating a cryptic t(12;21)(p13;q22), and also had loss of the ETV6 probe from the chromosome 12 not involved in the t(12;21). Seven cases were negative for fusion and had loss of an ETV6 signal, although one of the latter had a diminished ETV6 signal identified. To determine whether both PAX5-ETV6 and ETV6-RUNX1 rearrangements occurred in some patients, a diagnostic sample from each patient was analyzed by RT-PCR for the PAX5-ETV6 and ETV6-RUNX1 fusion genes. Primers from exon 3 of PAX5 and exon 3 of ETV6 were used for the PAX5-ETV6 analysis and from exon 5 of ETV6 and exon 4 of RUNX1 for the ETV6-RUNX1 analysis. Of the 20 cases, only 8 were RT-PCR positive for the PAX5-ETV6 fusion with the above primers; however, an additional 2 were RT-PCR positive with alternate primers, and all 10 of these were negative for the ETV6-RUNX1 fusion by RT-PCR. Of the remaining 10 patients, 9 were RT-PCR positive for the ETV6-RUNX1 fusion, including all of the ETV6-RUNX1 cases positive by FISH. The gene rearrangement associated with the dic(9;12) in these cases is not known. One patient was negative for both fusions by RT-PCR, negative by FISH for ETV6-RUNX1 rearrangement, yet had loss of an ETV6 signal. No cytogenetic differences could be seen between the 2 groups, either in the appearance of the dic(9;12) or in the other abnormalities identified. These results demonstrate the presence of two mutually exclusive dic(9;12) rearrangements in pediatric ALL; one associated with ETV6-RUNX1 rearrangement and one resulting in PAX5-ETV6 fusion. Both PAX5-ETV6 and ETV6-RUNX1 rearrangements are associated with a favorable prognosis. However, molecular analysis of the dic(9;12) patients must be performed to determine whether the dicentric chromosome results in PAX5-ETV6 fusion or whether the case has ETV6-RUNX1 fusion.

Imatinib at Weekly Dosage May Induce and Maintain Haematologic and Molecular Remission in Chronic Eosinophilic Leukemia Harbouring FIP1L1-PDGFRA Fusion Gene- An Extended Follow-up Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1755-1755
Author(s):  
Grzegorz Helbig ◽  
Malgorzata Calbecka ◽  
Justyna Gajkowska ◽  
Andrzej Moskwa ◽  
Alina Urbanowicz ◽  
...  
Keyword(s):  
Median Time ◽  
Fusion Gene ◽  
Hypereosinophilic Syndrome ◽  
Imatinib Treatment ◽  
Weekly Dose ◽  
Rt Pcr ◽  
Molecular Remission ◽  
Chronic Eosinophilic Leukemia ◽  
Weekly Dosage

Abstract Background. A small proportion of patients with hypereosinophilic syndrome (HES) demonstrate the presence of an interstitial deletion in chromosome 4 leading to the creation of the imatinib-responsive fusion gene- FIP1L1-PDGFRA (F/P). Recently, we showed that a single weekly dose of imatinib is sufficient to induce and maintain remission of chronic eosinophilic leukemia (CEL) with detectable F/P transcript. Here, we present data from 12 patients CEL and HES, 11 of which were F/P positive, who achieved a rapid complete haematologic remission (CHR) with daily imatinib treatment and remission was then maintained with a weekly imatinib schedule. Design and methods. Twelve patients, 11 out of 12 with detectable F/P were treated with imatinib at the initial doses varies between 100–400mg. There were 10 male and 2 female with a median age of 57 years (19–80). Median time to start imatinib was 23 months (1–204 months). The imatinib dose was de-escalated while patients remained in haematologic remission. As a response maintenance, once weekly imatinib was established in all cases. Results. All studied patients achieved a complete haematologic remission (CHR) and 100% of cases with detectable F/P fusion gene before imatinib, demonstrated a molecular remission determined by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. The breakpoints occured within exon 12 of PDGFRA whereas breakpoints dispersed across the FIP1L1 locus occuring between exons 10 and 13. Median time to achieve CHR was 13 days (4–90), and median time to molecular remission was 9 months (4–24). As a remission maintenance, imatinib doses were set at 100mg weekly in 9 pts and 200mg weekly in 3. With a median follow-up of 21 months (8–49 months) all pts remain in CHR. The FIP1L1-PDGFRA is undetectable in 11 patients by RT-PCR. Conclusions. Imatinib at weekly dosage may induce and maintain remission in patient with CEL expressing F/P fusion gene. This strategy appears to be safe and cost savings.

scholarly journals The Paradigm of Targeting an Oncogenic Tyrosine Kinase: Lesson from BCR-ABL

2021 ◽  
Author(s):  
Enrico Bracco ◽  
M. Shahzad Ali ◽  
Stefano Magnati ◽  
Giuseppe Saglio
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Kinase Activity ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Protein Tyrosine Phosphatases ◽  
Selective Inhibition ◽  
Tyrosine Kinase Activity

The aberrant tyrosine phosphorylation, either due to constitutive tyrosine kinases (TKs) or to inactivation of protein tyrosine phosphatases (PTPs), is a widespread feature of many cancerous cells. The BCR-ABL fusion protein, which arises from the Philadelphia chromosome, is a molecular distinct and peculiar trait of some kind of leukemia, namely Chronic Myeloid and Acute Lymphoblastic Leukemia, and displays constitutive tyrosine kinase activity. In the chapter, we will highlight the milestones that had led to the identification of the BCR-ABL fusion gene and its role as the only molecular pathogenic event sufficient to elicit and sustain chronic myeloid leukemia. We will also discuss the effort made to unveil the molecular mechanisms of action of the chimeric tyrosine kinase that eventually lead to aberrant cell proliferation and impaired cell-death. Furthermore, we will also review the lesson learned from the selective inhibition of BCR-ABL which currently represent a breakthrough in the treatment of several tumors characterized by defective tyrosine kinase activity.

scholarly journals Identification of a Novel HOOK3-FGFR1 Fusion Gene Involved in Activation of The NF-kappaB Pathway

2021 ◽  
Author(s):  
Xuehong Zhang ◽  
Furong Wang ◽  
Fanzhi Yan ◽  
Dan Huang ◽  
Haina Wang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Sanger Sequencing ◽  
Fusion Gene ◽  
Chromosome 8 ◽  
Antibody Array ◽  
Fish Analysis ◽  
Qrt Pcr ◽  
Healthy Donors ◽  
Recurrent Mutations ◽  
Nf Kappab

Abstract BackgroundRearrangements involving the fibroblast growth factor receptor 1 (FGFR1) gene result in 8p11 myeloproliferative syndrome (EMS), which is a rare and aggressive hematological malignancy that is often initially diagnosed as myelodysplastic syndrome (MDS). Clinical outcomes are typically poor due to relative resistance to tyrosine kinase inhibitors (TKIs) and rapid transformation to acute leukemia. Deciphering the transcriptomic signature of FGFR1 fusions may open new treatment strategies for FGFR1 rearrangement patients.MethodsDNA sequencing (DNA-seq) was performed for 20 MDS patients and whole exome sequencing (WES) was performed for one HOOK3-FGFR1 fusion positive patient. RNA sequencing (RNA-seq) was performed for 20 MDS patients and 8 healthy donors. Fusion genes were detected using the STAR-Fusion tool. Fluorescence in situ hybridization (FISH), quantitative real-time PCR (qRT-PCR), and Sanger sequencing were used to confirm the HOOK3-FGFR1 fusion gene. The phosphorylation antibody array was performed to validate the activation of nuclear factor-kappaB (NF-kappaB) signaling. ResultsWe identified frequently recurrent mutations of ASXL1 and U2AF1 in the MDS cohort, which is consistent with previous reports. We also identified a novel in-frame HOOK3-FGFR1 fusion gene in one MDS case with abnormal monoclonal B-cell lymphocytosis and ring chromosome 8. FISH analysis detected the FGFR1 break-apart signal in myeloid blasts only. qRT-PCR and Sanger sequencing confirmed the HOOK3-FGFR1 fusion transcript with breakpoints located at the 11th exon of HOOK3 and 10th exon of FGFR1, and Western blot detected the chimeric HOOK3-FGFR1 fusion protein that is presumed to retain the entire tyrosine kinase domain of FGFR1. The transcriptional feature of HOOK3-FGFR1 fusion was characterized by the significant enrichment of the NF-kappaB pathway by comparing the expression profiling of FGFR1 fusion positive MDS with 8 healthy donors and FGFR1 fusion negative MDS patients. Further validation by phosphorylation antibody array also showed NF-kappaB activation, as evidenced by increased phosphorylation of p65 (Ser 536) and of IKBalpha (Ser 32). ConclusionThe HOOK3-FGFR1 fusion gene may contribute to the pathogenesis of MDS and activate the NF-kappaB pathway. These findings highlight a potential novel approach for combination therapy for FGFR1 rearrangement patients.

scholarly journals Axl-Gas6 Interaction Counteracts E1A-Mediated Cell Growth Suppression and Proapoptotic Activity

1999 ◽  
Vol 19 (12) ◽  
pp. 8075-8082 ◽  
Author(s):  
Wei-Ping Lee ◽  
Yong Liao ◽  
Dan Robinson ◽  
Hsing-Jien Kung ◽  
Edison T. Liu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Growth Suppression ◽  
Serum Deprivation ◽  
Transcriptional Level ◽  
Rt Pcr ◽  
Degenerate Primers ◽  
Pcr Products ◽  
Her 2 ◽  
Induced Apoptosis

ABSTRACT The adenovirus type 5 early region 1A gene (E1A) has previously been known as an immortalization oncogene because E1A is required for transforming oncogenes, such as ras andE1B, to transform cells in primary cultures. However, E1A has also been shown to downregulate the overexpression of theHer-2/neu oncogene, resulting in suppression of transformation and tumorigenesis induced by that oncogene. In addition, E1A is able to promote apoptosis induced by anticancer drugs, irradiation, and serum deprivation. Many tyrosine kinases, such as the epidermal growth factor receptor, Her-2/Neu, Src, and Axl, are known to play a role in oncogenic signals in transformed cells. To study the mechanism underlying the E1A-mediated tumor-suppressing function, we exploited a modified tyrosine kinase profile assay (D. Robinson, F. Lee, T. Pretlow, and H.-J. Kung, Proc. Natl. Acad. Sci. USA 93:5958–5962, 1996) to identify potential tyrosine kinases regulated by E1A. Reverse transcription (RT)-PCR products were synthesized with two degenerate primers derived from the conserved motifs of various tyrosine kinases. A tyrosine kinase downregulated by E1A was identified by analyzing the AluI-digested RT-PCR products. We isolated the DNA fragment of interest and found that E1A negatively regulated the expression of the transforming receptor tyrosine kinase Axl at the transcriptional level. To study whether downregulation of the Axl receptor is involved in E1A-mediated growth suppression, we transfectedaxl cDNA into E1A-expressing cells (ip1-E1A) to establish cells that overexpressed Axl. The Axl ligand Gas6 triggered a greater mitogenic effect in these ip1-E1A-Axl cells than in ip1-E1A control cells and protected the Axl-expressing cells from serum deprivation-induced apoptosis. These results indicate that downregulation of the Axl receptor by E1A is involved in E1A-mediated growth suppression and E1A-induced apoptosis and thereby contributes to E1A’s antitumor activities.

Characterization of 14 NUP214-ABL1 Fusions in T-Cell Acute Lymphoblastic Leukaemia (T-ALL) Exhibits a Genomic Heterogeneity.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2075-2075
Author(s):  
Carlos Graux ◽  
Marina Lafage ◽  
Nicole Dastugue ◽  
Francine Mugneret ◽  
Roland Berger ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Cultured Cells ◽  
Outcome Data ◽  
Tyrosine Kinase Domain ◽  
Fish Analysis ◽  
Rt Pcr ◽  
Genomic Amplification ◽  
Chromosomal Alterations ◽  
Male Predominance

Abstract The recently described episomal amplification of the NUP214-ABL1 fusion in 6% of T-ALL leads to the expression of a constitutively activated chimeric tyrosine kinase sensitive to imatinib. We collected additional cases in order to better characterize this new entity with respect to genetic presentations and clinical course. We collected 14 new NUP214-ABL1 positive cases by FISH (LSI-BCR/ABL1 ES, Vysis and ABL1 break-apart home-made probes) or RT-PCR (fusion transcript) screening. FISH analysis detected episomal amplification of NUP214-ABL1 in 11 patients with a highly variable number of nuclei with amplification (<1% to 90%). Interestingly, one case showed a higher percentage of nuclei with amplification when using frozen non cultured cells rather than cultured fixed cells (10% vs 1%) suggesting loss of episomes during culture. FISH showed also intrachromosomal amplification of NUP214-ABL1 in two cases: one presented a HSR at the original 9q34 site without detectable episomes, the other associated HSR (probably on a chromosome 10), episomes (<1% of nuclei) and 9q34 chromosomal insertions including NUP214 and ABL3′ that encode the tyrosine kinase domain but not ABL5′, on variable chromosomes including 14p (33%). One NUP214-ABL1 RT-PCR positive case did not show any FISH aberration. Median age: 16 y (3–45) with a male predominance (10:4). There were no T-cell lymphoblastic lymphoma. Immunophenotype (EGIL): mature (n=2), cortical (n=6) or pre-T (n=4). Karyotype: structural chromosomal alterations in 8 patients (including 4 with 10q24/HOX11 rearrangements), only numerical chromosomal alterations in 4 (including 2 with + 8), normal in 1, failed in 1. All samples with available information (10/14) showed a HOX11 or HOX11L2 abnormality. Among the 13 cases with available outcome data, we observed 5 early relapses, including both patients with NUP214-ABL1 HSR, and 1 refractory ALL. These observations emphasize the interest of combining both (quantitative) RT-PCR and FISH for the screening and characterisation of NUP214-ABL1 fusion and amplification, demonstrate the coexistence of different NUP214-ABL1 genomic presentations in one patient (episomal amplification, 9q34 insertions, HSR) compatible with the model in which genomic amplification start with episome formation in order to create the NUP214-ABL1 fusion followed by their amplification and optional secondary reintegration, confirm occurrence of NUP214-ABL1 in T-ALL with HOX11 and HOX11L2 involvement, raise the question of the rather worse prognosis for cases with intrachromosomal amplification as previously suggested, raise the signification of minor NUP214-ABL1 clones and variable genomic presentations in the leukemogenesis of this subgroup of T-ALL that could potentially benefit from imatimib. ° on behalf of the GFCH (Groupe Francophone de Cytogénétique Hématologique) and the BCGHO (Belgian Cytogenetic Group for Hematology and Oncology).

scholarly journals Nanostring-based screening for tyrosine kinase fusions in inflammatory myofibroblastic tumors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Taisei Kurihara ◽  
Yoshiyuki Suehara ◽  
Keisuke Akaike ◽  
Takuo Hayashi ◽  
Shinji Kohsaka ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Rna Sequencing ◽  
Fusion Gene ◽  
Rt Pcr ◽  
Anaplastic Lymphoma ◽  
Inflammatory Myofibroblastic Tumors ◽  
Polymerase Chain ◽  
Lymphoplasmacytic Infiltration ◽  
Tyrosine Receptor Kinase

Abstract Gene expression imbalances were measured for tyrosine kinase (TK) genes using Nanostring in 19 samples of inflammatory myofibroblastic tumor (IMT). All cases were immunohistochemically stained with anaplastic lymphoma kinase (ALK) and pan-tropomyosin-related-kinase (pan-Trk) antibodies. Five cases with imbalanced ALK expression, reported with Nanostring, were tested using fluorescence in situ hybridization (FISH); two cases with imbalanced neurotrophic tyrosine receptor kinase 3 (NTRK3) expression were tested using reverse transcription-polymerase chain reaction (RT-PCR). One case with imbalanced expression for ROS proto-oncogene 1 (ROS1) was tested using RNA sequencing and RT-PCR. TK fusions were detected in all cases with imbalanced TK expression. RNA sequencing detected a FN1–ROS1 fusion gene in an adult IMT case. IMT with ALK rearrangement showed myofibroblast-dominant features. IMT with ETV6–NTRK3 fusion showed prominent lymphoplasmacytic infiltration with scattered myofibroblasts. Pan-Trk IHC revealed only scattered positively stained cells in IMT with ETV6–NTRK3 fusion gene. ROS1-positive IMT showed myofibroblast-dominant features.

scholarly journals Role of Dok-1 and Dok-2 in Leukemia Suppression

2004 ◽  
Vol 200 (12) ◽  
pp. 1689-1695 ◽  
Author(s):  
Masaru Niki ◽  
Antonio Di Cristofano ◽  
Mingming Zhao ◽  
Hiroaki Honda ◽  
Hisamaru Hirai ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Cellular Proliferation ◽  
Myelogenous Leukemia ◽  
Myeloproliferative Disease ◽  
Kinase Activation ◽  
Abl Tyrosine Kinase ◽  
Long Latency

Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210bcr/abl oncoprotein that shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Although several p210bcr/abl substrates have been identified, their relevance in the pathogenesis of the disease is unclear. We have identified a family of proteins, Dok (downstream of tyrosine kinase), coexpressed in hematopoietic progenitor cells. Members of this family such as p62dok(Dok-1) and p56dok-2(Dok-2) associate with the p120 rasGTPase-activating protein (rasGAP) upon phosphorylation by p210bcr/abl as well as receptor and nonreceptor tyrosine kinases. Here, we report the generation and characterization of single and double Dok-1 or Dok-2 knockout (KO) mutants. Single KO mice displayed normal steady-state hematopoiesis. By contrast, concomitant Dok-1 and Dok-2 inactivation resulted in aberrant hemopoiesis and Ras/MAP kinase activation. Strikingly, all Dok-1/Dok-2 double KO mutants spontaneously developed transplantable CML-like myeloproliferative disease due to increased cellular proliferation and reduced apoptosis. Furthermore, Dok-1 or Dok-2 inactivation markedly accelerated leukemia and blastic crisis onset in Tec-p210bcr/abl transgenic mice known to develop, after long latency, a myeloproliferative disorder resembling human CML. These findings unravel the critical and unexpected role of Dok-1 and Dok-2 in tumor suppression and control of the hematopoietic compartment homeostasis.

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