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.

Acute Mixed Lineage Leukemia With an inv(8)(p11q13) Resulting in Fusion of the Genes for MOZ and TIF2

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 2118-2122 ◽  
Author(s):  
Jian Liang ◽  
Leonard Prouty ◽  
B. Jill Williams ◽  
Mark A. Dayton ◽  
Kerry L. Blanchard
Keyword(s):  
Acute Leukemia ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Mixed Lineage Leukemia ◽  
Chromosome 8 ◽  
Acute Monocytic Leukemia ◽  
Fish Analysis ◽  
Creb Binding Protein ◽  
Monocytic Leukemia ◽  
Interaction Domain

Chromosomal abnormalities in acute leukemia have led to the discovery of many genes involved in normal hematopoiesis and in malignant transformation. We have identified the fusion partners in an inv(8)(p11q13) from a patient with acute mixed lineage leukemia. We show by fluorescence in situ hybridization (FISH) analysis, Southern blotting, and reverse transcriptase-polymerase chain reaction (RT-PCR) that the genes for MOZ, monocytic leukemiazinc finger protein, and TIF2,transcriptional intermediary factor 2, are involved in the inv(8)(p11q13). We demonstrate that the inversion creates a fusion between the 5′ end of MOZ mRNA and the 3′ end of TIF2 mRNA maintaining the translational frame of the protein. The predicted fusion protein contains the zinc finger domains, the nuclear localization domains, the histone acetyltransferase (HAT) domain, and a portion of the acidic domain ofMOZ, coupled to the CREB-binding protein (CBP) interaction domain and the activation domains of TIF2. The breakpoint is distinct from the breakpoint in the t(8;16)(p11;p13) translocation in acute monocytic leukemia with erythrophagocytosis that fuses MOZ with CBP. The reciprocalTIF2-MOZ fusion gene is not expressed, perhaps as a result of a deletion near the chromosome 8 centromere. TheMOZ-TIF2 fusion is one of a new family of chromosomal rearrangements that associate HAT activity, transcriptional coactivation, and acute leukemia. © 1998 by The American Society of Hematology.

Acute Mixed Lineage Leukemia With an inv(8)(p11q13) Resulting in Fusion of the Genes for MOZ and TIF2

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 2118-2122 ◽  
Author(s):  
Jian Liang ◽  
Leonard Prouty ◽  
B. Jill Williams ◽  
Mark A. Dayton ◽  
Kerry L. Blanchard
Keyword(s):  
Acute Leukemia ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Mixed Lineage Leukemia ◽  
Chromosome 8 ◽  
Acute Monocytic Leukemia ◽  
Fish Analysis ◽  
Creb Binding Protein ◽  
Monocytic Leukemia ◽  
Interaction Domain

Abstract Chromosomal abnormalities in acute leukemia have led to the discovery of many genes involved in normal hematopoiesis and in malignant transformation. We have identified the fusion partners in an inv(8)(p11q13) from a patient with acute mixed lineage leukemia. We show by fluorescence in situ hybridization (FISH) analysis, Southern blotting, and reverse transcriptase-polymerase chain reaction (RT-PCR) that the genes for MOZ, monocytic leukemiazinc finger protein, and TIF2,transcriptional intermediary factor 2, are involved in the inv(8)(p11q13). We demonstrate that the inversion creates a fusion between the 5′ end of MOZ mRNA and the 3′ end of TIF2 mRNA maintaining the translational frame of the protein. The predicted fusion protein contains the zinc finger domains, the nuclear localization domains, the histone acetyltransferase (HAT) domain, and a portion of the acidic domain ofMOZ, coupled to the CREB-binding protein (CBP) interaction domain and the activation domains of TIF2. The breakpoint is distinct from the breakpoint in the t(8;16)(p11;p13) translocation in acute monocytic leukemia with erythrophagocytosis that fuses MOZ with CBP. The reciprocalTIF2-MOZ fusion gene is not expressed, perhaps as a result of a deletion near the chromosome 8 centromere. TheMOZ-TIF2 fusion is one of a new family of chromosomal rearrangements that associate HAT activity, transcriptional coactivation, and acute leukemia. © 1998 by The American Society of Hematology.

FLT3 Is Fused to ETV6 in a Myeloproliferative Disorder with a t(12;13)(p13;q12) Translocation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2901-2901
Author(s):  
Hoang Anh Vu ◽  
Phan Thi Xinh ◽  
Seiko Shimizu ◽  
Michihiko Masuda ◽  
Toshiko Motoji ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Blot Analysis ◽  
Fusion Proteins ◽  
Fusion Gene ◽  
Hematologic Malignancies ◽  
Myeloproliferative Disorder ◽  
Tyrosine Kinase Domain ◽  
Common Mutation ◽  
Fish Analysis ◽  
Fusion Partner

Abstract The FLT3, located at band 13q12 and encoding a receptor tyrosine kinase (RTK), is one of the most frequently mutated genes in hematologic malignancies including ALL, MDS, and AML. The most common mutation of the FLT3 is an internal tandem duplication in exons 14 and 15, whereas other mutations have also been found at and around codon 835 of exon 20. These activating mutations promote constitutive RTK activity in the absence of ligand, proposing FLT3 as an attractive therapeutic target for directed inhibition. However, many questions with regards to the biology of FLT3 and its role in leukemogenesis remain to be clarified. Despite its highly frequent mutations, FLT3 has never been reported to fuse to any other genes, a phenomenon usually observed in other RTKs. Here, we report a case of a novel fusion gene between FLT3 and ETV6 at 12p13, a well-known target for a number of translocations. The patient, a 68-year-old female, was diagnosed as myeloproliferative disorder with hypereosinophilia in May 2002. Peripheral blood showed WBC 33.6x106/L (3% myelocytes, 33.5% neutrophils, 54% eosinophils, 1.5% basophils, 1.0% monocytes and 7% lymphocytes), Hb 119g/L and platelet counts 5,450x106/L. The bone marrow (BM) was marked hypercellular with 0.9% blasts, 6.0% promyelocytes, 15.6% myelocytes, 8.1% immature eosinophils and 19.2% mature eosinophils. Karyotype of BM cells was 46, XX, t(12;13)(p13.1;q12.3–13)[28]/46, XX[2]. Under the suspicion of Ph-negative CML, she was treated with IFNα with no response. Then, HU was started and her WBC decreased to 30x106/L. FISH analysis showed that the breakpoint at 12p13 occurred within ETV6, while the breakpoints at 13q12 occurred at two locations, within FLT3 or CDX2. To identify the fusion partner of ETV6, 3′-RACE PCR was performed. Sequence analysis of PCR-products revealed 4 types of ETV6/FLT3 transcripts. These fusion transcripts were confirmed by Northern blot analysis. Each ETV6/FLT3 transcript contained the entire helix-loop-helix domain of ETV6 (exons 1 to 4 or 5) and almost all of the functional domains of FLT3 including the tyrosine kinase domain (from exons 14, 16 or 17), suggesting that the resultant chimeric protein would be constitutively activated FLT3 kinase. Of them, three are in-frame fusion, presumably encoding for the approximately 58, 62, and 83 kD fusion proteins. However, Western blot analysis showed only expression of the 58 and 83 kD proteins. RT-PCR detected the reciprocal FLT3/ETV6 transcript, comprising the FLT3 exons 1 to 13 frameshifly fused to the ETV6 exons 6 to 8, within which a stop codon appeared at codon 33- downstream from the fusion point. Functional studies to assess the oncogenic properties of these fusion proteins are now in progress. Our findings provide an evidence that FLT3 is also involved in hematologic malignancies as a fusion gene.

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.

scholarly journals Break–apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cut-off level for RET/PTC rearrangements

2015 ◽  
Vol 172 (5) ◽  
pp. 571-582 ◽  
Author(s):  
Chiara Colato ◽  
Caterina Vicentini ◽  
Silvia Cantara ◽  
Serena Pedron ◽  
Paolo Brazzarola ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Chromosomal Rearrangements ◽  
Study Cohort ◽  
Fish Analysis ◽  
Papillary Thyroid ◽  
Qrt Pcr ◽  
Molecular Events ◽  
On The Road

ObjectiveChromosomal rearrangements of theRETproto-oncogene is one of the most common molecular events in papillary thyroid carcinoma (PTC). However, their pathogenic role and clinical significance are still debated. This study aimed to investigate the prevalence of RET/PTC rearrangement in a cohort ofBRAFWT PTCs by fluorescencein situhybridization (FISH) and to search a reliable cut-off level in order to distinguish clonal or non-clonal RET changes.DesignFortyBRAFWT PTCs were analyzed by FISH for RET rearrangements. As controls, sixBRAFV600E mutated PTCs, 13 follicular adenomas (FA), and ten normal thyroid parenchyma were also analyzed.MethodsWe performed FISH analysis on formalin-fixed, paraffin-embedded tissue using a commercially available RET break–apart probe. A cut-off level equivalent to 10.2% of aberrant cells was accepted as significant. To validate FISH results, we analyzed the study cohort by qRT-PCR.ResultsSplit RET signals above the cut-off level were observed in 25% (10/40) of PTCs, harboring a percentage of positive cells ranging from 12 to 50%, and in one spontaneous FA (1/13, 7.7%). Overall, the data obtained by FISH matched well with qRT-PCR results. Challenging findings were observed in five cases showing a frequency of rearrangement very close to the cut-off.ConclusionsFISH approach represents a powerful tool to estimate the ratio between broken and non-broken RET tumor cells. Establishing a precise FISH cut-off may be useful in the interpretation of the presence of RET rearrangement, primarily when this strategy is used for cytological evaluation or for targeted therapy.

miR-26b Regulates Osteoactivin (OA)-Induced Bone Marrow Mesenchymal Cells (BMSCs) Osteogenic Differentiation by Targeting Fms-Like Tyrosine Kinase 3 (FLT3)/AXL

2021 ◽  
Vol 11 (9) ◽  
pp. 1774-1779
Author(s):  
Feng Sun ◽  
Tianwen Huang ◽  
Jianhui Shi ◽  
Tianli Wei ◽  
Haiwei Zhang
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Tyrosine Kinase ◽  
Osteogenic Differentiation ◽  
Signaling Pathway ◽  
Formation Process ◽  
Mesenchymal Cells ◽  
Mrna Levels ◽  
Qrt Pcr ◽  
Bone Marrow Mesenchymal Cells

Osteoactivin (OA) plays a key role in osteogenic differentiation. miR-26b is elevated in the bone formation process of BMSCs, but whether it is involved in this process is unclear. Bone formation is regulated by FLT3/AXL signaling pathway, which may be a potential target of miR-26b. qRT-PCR detected miR-26b mRNA levels and bone formation-related genes or FLT3/AXL signaling pathway-related genes. Bone formation was analyzed by staining and FLT3/AXL signaling was evaluated along with analysis of miR-26b’s relation with LT3/AXL. miR-26b was significantly elevated in OA-induced bone formation of BMSCs, which can be promoted by miR-26b mimics. When miR-26b was overexpressed, FLT3/AXL signaling pathway was activated. miR-26b can ameliorate Dex-induced osteo-inhibition. miR-26b promotes bone formation of BMSCs by directly targeting FLT3/AXL signaling pathway, suggesting that miR-26b might be a target for inducing osteogenic differentiation.

scholarly journals Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

2020 ◽  
Vol 21 (16) ◽  
pp. 5776 ◽  
Author(s):  
Lukasz Komorowski ◽  
Klaudyna Fidyt ◽  
Elżbieta Patkowska ◽  
Malgorzata Firczuk
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Great Majority ◽  
Metabolic Reprogramming ◽  
Chromosome 9 ◽  
Treatment Protocols ◽  
Resistant Disease

Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (BCR) gene on chromosome 9 and ABL proto-oncogene 1 (ABL1) gene on chromosome 22. The fusion gene, BCR-ABL1, is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the BCR gene, different isoforms of BCR-ABL1 exist, with p210 and p190 being the most prevalent. P210 isoform is the hallmark of chronic myeloid leukemia (CML), while p190 isoform is expressed in majority of Ph-positive B cell acute lymphoblastic leukemia (Ph+ B-ALL) cases. The crucial component of treatment protocols of CML and Ph+ B-ALL patients are tyrosine kinase inhibitors (TKIs), drugs which target both BCR-ABL1 isoforms. While TKIs therapy is successful in great majority of CML patients, Ph+ B-ALL often relapses as a drug-resistant disease. Recently, the high-throughput genomic and proteomic analyses revealed significant differences between CML and Ph+ B-ALL. In this review we summarize recent discoveries related to differential signaling pathways mediated by different BCR-ABL1 isoforms, lineage-specific genetic lesions, and metabolic reprogramming. In particular, we emphasize the features distinguishing Ph+ B-ALL from CML and focus on potential therapeutic approaches exploiting those characteristics, which could improve the treatment of Ph+ B-ALL.

scholarly journals Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

2019 ◽  
Vol 20 (24) ◽  
pp. 6141 ◽  
Author(s):  
Luana Bavaro ◽  
Margherita Martelli ◽  
Michele Cavo ◽  
Simona Soverini
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Dismal Prognosis

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, some patients may not respond (primary resistance) or may relapse after an initial response (secondary resistance). In a small proportion of cases, development of resistance is accompanied or shortly followed by progression from chronic to blastic phase (BP), characterized by a dismal prognosis. Evolution from CP into BP is a multifactorial and probably multistep phenomenon. Increase in BCR-ABL1 transcript levels is thought to promote the onset of secondary chromosomal or genetic defects, induce differentiation arrest, perturb RNA transcription, editing and translation that together with epigenetic and metabolic changes may ultimately lead to the expansion of highly proliferating, differentiation-arrested malignant cells. A multitude of studies over the past two decades have investigated the mechanisms underlying the closely intertwined phenomena of drug resistance and disease progression. Here, we provide an update on what is currently known on the mechanisms underlying progression and present the latest acquisitions on BCR-ABL1-independent resistance and leukemia stem cell persistence.

Molecular Monitoring and Mutations in Chronic Myeloid Leukemia: How to Get the Most out of Your Tyrosine Kinase Inhibitor

2014 ◽  
pp. 167-175 ◽  
Author(s):  
Michele Baccarani ◽  
Simona Soverini ◽  
Caterina De Benedittis
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Sanger Sequencing ◽  
Mutational Analysis ◽  
Residual Disease ◽  
Kinase Domain ◽  
Response To Treatment ◽  
Molecular Response ◽  
Therapeutic Decisions

The course of chronic myeloid leukemia (CML) and the response to treatment with tyrosine kinase inhibitors (TKIs) are best monitored and assessed using two molecular tests: the first is real-time quantitative reverse transcription-polymerase chain reaction (RQ-PCR), which measures the size of residual disease that is expressed as BCR-ABL1% (the ratio between BCR-ABL1 and a control gene) and the other is mutational analysis by Sanger sequencing, which checks for the presence of BCR-ABL1 kinase domain point mutations. Both tests are technically demanding and require a high level of specialization and standardization. RQ-PCR, when performed on a regular basis, allows for the defining of molecular response (MR) levels as log reduction from a standardized baseline: major molecular response (MMR or MR3) that is the best predictor of survival; and the deeper molecular response (MR4, MR4.5, and MR5) that is necessary to enroll a patient in a trial aiming at treatment-free remission (TFR). Mutational analysis, to be performed in case of failure or warning by Sanger sequencing, allows for screening of the BCR-ABL1 kinase domain for mutations conferring resistance to TKIs. Since different mutations have different degrees of sensitivity to each of the currently available TKI, the knowledge of BCR-ABL1 kinase domain–mutation status is necessary for subsequent treatment choice. Optimal patient management requires that MR and mutational information be rationally interpreted at both the technical and at the biologic level, and put into context—therapeutic decisions also take into account other factors, such as age, comorbidities, side effects, compliance, and treatment-related complications.

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.

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