The diagnosis of myoepithelial (ME) tumors outside salivary glands remains challenging, especiall... more The diagnosis of myoepithelial (ME) tumors outside salivary glands remains challenging, especially in unusual clinical presentations, such as bone or visceral locations. A few reports have indicated EWSR1 gene rearrangement in soft tissue ME tumors, and, in one case each, the fusion partner was identified as either PBX1 or ZNF444. However, larger studies to investigate if these genetic abnormalities are recurrent or restricted to tumors in soft tissue locations are lacking. Sixty-six ME tumors mainly from soft tissue (71%), but also from skin, bone and visceral locations, characterized by classic morphologic features and supporting immunoprofile were studied. Gene rearrangements in EWSR1, FUS, PBX1 and ZNF444 were investigated by FISH. EWSR1 gene rearrangement was detected in 45% of the cases. A EWSR1-POU5F1 fusion was identified in a pediatric soft tissue tumor by 3'RACE and subsequently confirmed in four additional soft tissue tumors in children and young adults. An EWSR1-PBX1 fusion was seen in five cases, while EWSR1-ZNF444 and FUS gene rearrangement was noted in one pulmonary tumor each. In conclusion, EWSR1 gene rearrangement is a common event in ME tumors arising outside salivary glands, irrespective of anatomic location. EWSR1 negative tumors were more often benign, superficially located, and showed ductal differentiation, suggesting the possibility of genetically distinct groups. A subset of soft tissue ME tumors with clear cell morphology harbor an EWSR1-POU5F1 fusion, which can be used as a molecular diagnostic test in difficult cases. These findings do not support a pathogenetic relationship between soft tissue ME tumors and their salivary gland counterparts.
Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2011
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 ... more This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
Cytogenetics has long represented a critical component in the clinical evaluation of hematologic ... more Cytogenetics has long represented a critical component in the clinical evaluation of hematologic malignancies. Chromosome banding studies provide a simultaneous snapshot of genome-wide copy number and structural variation, which have been shown to drive tumorigenesis, define diseases, and guide treatment. Technological innovations in sequencing have ushered in our present-day clinical genomics era. With recent publications highlighting novel sequencing technologies as alternatives to conventional cytogenetic approaches, we, an international consortium of laboratory geneticists, pathologists, and oncologists, describe herein the advantages and limitations of both conventional chromosome banding and novel sequencing technologies and share our considerations on crucial next steps to implement these novel technologies in the global clinical setting for a more accurate cytogenetic evaluation, which may provide improved diagnosis and treatment management. Considering the clinical, logisti...
The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a col... more The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter appr...
BCR-ABL1 kinase inhibitors have improved the prognosis of Philadelphia-chromosome-positive (Ph+)-... more BCR-ABL1 kinase inhibitors have improved the prognosis of Philadelphia-chromosome-positive (Ph+)-acute lymphoblastic leukemia (ALL). Ph-like (or BCR-ABL1-like) ALL does not express BCR-ABL1 but commonly harbors other genomic alterations of signaling molecules that may be amenable to therapy. Here, we report a case with a NUP214-ABL1 fusion detected at relapse by multiplexed, targeted RNA sequencing. It had escaped conventional molecular work-up at diagnosis, including cytogenetic analysis and fluorescence in situ hybridization for ABL1 rearrangements. The patient had responded poorly to initial multi-agent chemotherapy and inotuzumab immunotherapy at relapse before the fusion was revealed. The addition of dasatinib targeting NUP214-ABL1 to inotuzumab resulted in complete molecular remission, but recurrence occurred rapidly with dasatinib alone. However, deep molecular remission was recaptured with a combination of blinatumomab and ponatinib, so he could proceed to allotransplantatio...
Key Points Targeted RNA sequencing detected a cryptic G3BP1-PDGFRB rearrangement in a myeloid neo... more Key Points Targeted RNA sequencing detected a cryptic G3BP1-PDGFRB rearrangement in a myeloid neoplasm with eosinophilia and normal FISH studies. Consistent with the patient’s response to imatinib, we demonstrate this rearrangement is oncogenic and sensitive to TKI in cell culture.
Cytologic and cytogenetic results obtained from patients fulfilling the FAB criteria for the diag... more Cytologic and cytogenetic results obtained from patients fulfilling the FAB criteria for the diagnosis of acute nonlymphocytic leukemia (ANLL) of megakaryocytic lineage (ANLL-M7) are reported. Eleven cases were de novo ANLL-M7, of whom three presented with acute myelofibrosis. Four cases were megakaryoblastic transformations of chronic myelogenous leukemia (two cases), refractory anemia with excess of blasts (one case), and polycythemia vera (one case). Four patients showed a minority of granular blasts, with occasional Auer rods in one. Positive myeloperoxidase and/or sudan black-B stainings and CD13 positivity in these cases were consistent with the presence of a myeloid involvement. Morphologic evidence of associated myelodysplastic features was detected in all evaluable patients with de novo ANLL-M7. These cytologic findings indicate that ANLL-M7 may frequently represent a multilineage proliferation. Cytogenetic studies revealed -7/7q- and +8, alone or in combination with additi...
This article (1) has been retracted at the request of the editors. The editors were made aware of... more This article (1) has been retracted at the request of the editors. The editors were made aware of concerns regarding potential manipulation of data in the article. An internal review by the editors determined that multiple Gapdh bands appear to be duplicated in Fig. 3A. In addition, the same g-tubulin Western blot band appears to be duplicated multiple times in Fig. 3B. The authors were not able to provide the original data to dispel these concerns.
Eighty-eight endometrial specimens from 36 postmenopausal breast cancer patients treated with tam... more Eighty-eight endometrial specimens from 36 postmenopausal breast cancer patients treated with tamoxifen were investigated cytogenetically and molecularly using fluorescence in situ hybridization with appropriate probes for the HMGIC and HMGIY genes. Twenty control specimens, 10 endometrial polyps, and 10 endometrial biopsy specimens were investigated in the same way. Of the 88 specimens, 44 were from endometrial polyps; 3 were from endocervical polyps; 7 were from cystic endometrium; 30 were from normal or atrophic endometrium, normal endocervix, or myometrium; and 4 were from endometrial carcinomas. Chromosome investigation of the endometrial polyps showed the nature of the chromosome changes in tamoxifen-induced polyps to be the same as that in the controls and in sporadic endometrial polyps described in the literature. HMGIC and HMGIY gene rearrangements in both groups were identical as shown by fluorescence in situ hybridization, which also allowed for the detection of seven hid...
Next generation sequencing (NGS) is increasingly being used clinically to characterize the molecu... more Next generation sequencing (NGS) is increasingly being used clinically to characterize the molecular alterations found in patients' tumors. These testing results have the potential to affect clinical care by guiding therapeutic approaches based upon genotype. NGS based testing approaches have a distinct advantage over provider-ordered single gene testing in that they can detect unexpected, yet clinically important genetic changes. Here, we illustrate this principle with the case of a 33-year-old man with myeloid sarcoma that was refractory to six different chemotherapeutic regimens. Our clinical NGS assay detected an unanticipated FIP1L1-PDGFRA rearrangement in his tumor. The patient was immediately placed on Imatinib therapy to which he responded, and remains in remission 10 months after the rearrangement was initially detected.
Klinefelter syndrome (KS), a 47,XXY chromosomal abnormality, has been shown to be associated with... more Klinefelter syndrome (KS), a 47,XXY chromosomal abnormality, has been shown to be associated with a number of malignancies, but has not been linked to acute leukemias to date. We present a case of a 54-year-old male diagnosed with acute myeloid leukemia (AML) with monocytic differentiation, whose cytogenetic and subsequent FISH analyses revealed a constitutional 47,XXY karyotype. We also review and discuss relevant prior literature.
Dermatofibrosarcoma protuberans (DFSP) and giant cell fibroblastoma (GCF) are recurrent, infiltra... more Dermatofibrosarcoma protuberans (DFSP) and giant cell fibroblastoma (GCF) are recurrent, infiltrative skin tumors that presently are treated with surgery. DFSP and GCF tumors are genetically characterized by chromosomal rearrangements fusing the collagen type Ialpha1 (COLIA1) gene to the platelet-derived growth factor B-chain (PDGFB) gene. It has been shown that the resulting COL1A1/PDGF-B fusion protein is processed to mature PDGF-BB. Autocrine PDGF receptor stimulation has therefore been predicted to contribute to DFSP and GCF tumor development and growth. Here we demonstrate presence of activated PDGF receptors in primary cultures derived from six different DFSP and GCF tumors. Three of the primary cultures were further characterized; their in vitro growth displayed an increased sensitivity to treatment with the PDGF receptor tyrosine kinase inhibitor STI571, as compared with normal fibroblasts. Transplantable tumors, displaying a DFSP-like histology, were established from one of...
Aberrations of the HMGIC gene, encoding an architectural transcription factor and located in the ... more Aberrations of the HMGIC gene, encoding an architectural transcription factor and located in the chromosomal region 12q15, are very frequent among benign mesenchymal tumors, such as lipomas, uterine leiomyomas, or pulmonary chondroid hamartomas. These HMGIC aberrations are caused by characteristic structural chromosomal aberrations, either visible by conventional cytogenetics or as cryptic abnormalities. Some of these aberrations of chromosome 12 are not specific for particular tumor entities but can occur in a variety of tumors with HMGIC abnormalities. One such example is the pericentric inversion inv(12)(p11.2q15). Starting from the ectopic sequence derived from an HMGIC fusion transcript of an aggressive angiomyxoma with such an inversion we established three PAC clones covering the breakpoint region 12p11 and cloned part of a yet unknown gene in 12p11.2, which is fused to the third exon of HMGIC. Using fluorescence in situ hybridization with these PACs we were able to show that...
Proceedings of the National Academy of Sciences, 2001
Endometrial stromal tumors are divided into three types: benign stromal nodules, endometrial stro... more Endometrial stromal tumors are divided into three types: benign stromal nodules, endometrial stromal sarcomas, and undifferentiated endometrial sarcomas. A variety of cytogenetic abnormalities involving chromosome 7 have been reported in endometrial stromal sarcomas, including a recurrent t(7;17)(p15;q21). We have identified two zinc finger genes, which we have termed JAZF1 and JJAZ1 , at the sites of the 7p15 and 17q21 breakpoints. Analyses of tumor RNA indicate that a JAZF1 / JJAZ1 fusion is present in all types of endometrial stromal tumors; however, the fusion appears to be rarer among endometrial stromal sarcomas that would be considered high-grade according to certain classification schemes. These findings suggest that the less malignant endometrial stromal tumors may evolve toward more malignant types, but that some endometrial stromal sarcomas with relatively abundant mitotic activity may compose a biologically distinct group.
Proceedings of the National Academy of Sciences, 2009
The prognosis for adults with precursor B-cell acute lymphoblastic leukemia (B-ALL) remains poor,... more The prognosis for adults with precursor B-cell acute lymphoblastic leukemia (B-ALL) remains poor, in part from a lack of therapeutic targets. We identified the type I cytokine receptor subunit CRLF2 in a functional screen for B-ALL–derived mRNA transcripts that can substitute for IL3 signaling. We demonstrate that CRLF2 is overexpressed in approximately 15% of adult and high-risk pediatric B-ALL that lackMLL, TCF3, TEL,andBCR/ABLrearrangements, but not in B-ALL with these rearrangements or other lymphoid malignancies. CRLF2 overexpression can result from translocation with theIGHlocus or intrachromosomal deletion and is associated with poor outcome. CRLF2 overexpressing B-ALLs share a transcriptional signature that significantly overlaps with a BCR/ABL signature, and is enriched for genes involved in cytokine receptor and JAK-STAT signaling. In a subset of cases, CRLF2 harbors a Phe232Cys gain-of-function mutation that promotes constitutive dimerization and cytokine independent grow...
Aneurysmal bone cysts (ABC) are locally aggressive bone tumors that often feature chromosome 17p1... more Aneurysmal bone cysts (ABC) are locally aggressive bone tumors that often feature chromosome 17p13 rearrangements. One of the ABC 17p13 rearrangementst(16;17)(q22;p13)-was recently shown to create a CDH11-USP6 fusion in which the USP6/TRE17 oncogene is overexpressed through juxtaposition with the CDH11 promoter. Herein, we characterize four different ABC translocations involving 17p13, and we show that each is associated with a novel USP6 fusion oncogene. Specifically, we demonstrate that t(1;17), t(3;17), t(9;17), and t(17;17) result in USP6 fusions with TRAP150 (thyroid receptor-associated protein 150), ZNF9 (ZiNc Finger 9), Osteomodulin, and COL1A1 (Collagen 1A1), respectively. The oncogenic mechanism in these fusion genes is akin to CDH11-USP6, with the USP6 coding sequences juxtaposed to the promoter regions in each of the four novel translocation partners. The novel fusion partners appear well suited to drive USP6 transcription in the bone/ mesenchymal context: osteomodulin is expressed strongly in osteoblastic lineages, and the COL1A1 promoter has an oncogenic role in the mesenchymal cancer dermatofibrosarcoma protuberans. In summary, these studies show that USP6 oncogenic activation results from heterogeneous genomic mechanisms involving USP6 transcriptional upregulation by juxtaposition with ectopic promoters.
Apart from its hormone responsiveness, little about the pathobiology of intravenous leiomyomatosi... more Apart from its hormone responsiveness, little about the pathobiology of intravenous leiomyomatosis (IVL), a rare smooth muscle proliferation, is known. We investigated the cytogenetics and molecular biology of IVL in a 40-year-old female who presented with an abrupt onset of dyspnea. In addition to the intracaval tumor mass composed of histologically benign smooth muscle, four distinct retroperitoneal "fibroids" were cytogenetically investigated. An identical abnormal karyotype, 45,XX,der(14)t(12;14)(q15;q24),-22, was observed in all five specimens. Fluorescence in situ hybridization revealed three copies of HMGIC (alias HMGA2), two on the normal chromosomes 12 at 12q15, as well as another on the der(14) in the breakpoint region, suggesting that the 12q breakpoint occurred 5' (centromeric) to HMGIC (HMGA2), as has been frequently observed in uterine leiomyoma. Such similarity in chromosomal rearrangements suggests that there may be a pathogenetic relationship between IVL and uterine leiomyomata with t(12;14). Skewed X inactivation was observed in each tumor sample, but not in the myometrium. In each tumor, the lower molecular weight allele of HUMARA was nonrandomly inactivated. This pattern of X inactivation is most consistent with origin from a single transformation event, and in this regard, IVL more closely resembles disseminated peritoneal leiomyomatosis than typical uterine leiomyomata.
Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely t... more Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing transdifferentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.
The diagnosis of myoepithelial (ME) tumors outside salivary glands remains challenging, especiall... more The diagnosis of myoepithelial (ME) tumors outside salivary glands remains challenging, especially in unusual clinical presentations, such as bone or visceral locations. A few reports have indicated EWSR1 gene rearrangement in soft tissue ME tumors, and, in one case each, the fusion partner was identified as either PBX1 or ZNF444. However, larger studies to investigate if these genetic abnormalities are recurrent or restricted to tumors in soft tissue locations are lacking. Sixty-six ME tumors mainly from soft tissue (71%), but also from skin, bone and visceral locations, characterized by classic morphologic features and supporting immunoprofile were studied. Gene rearrangements in EWSR1, FUS, PBX1 and ZNF444 were investigated by FISH. EWSR1 gene rearrangement was detected in 45% of the cases. A EWSR1-POU5F1 fusion was identified in a pediatric soft tissue tumor by 3'RACE and subsequently confirmed in four additional soft tissue tumors in children and young adults. An EWSR1-PBX1 fusion was seen in five cases, while EWSR1-ZNF444 and FUS gene rearrangement was noted in one pulmonary tumor each. In conclusion, EWSR1 gene rearrangement is a common event in ME tumors arising outside salivary glands, irrespective of anatomic location. EWSR1 negative tumors were more often benign, superficially located, and showed ductal differentiation, suggesting the possibility of genetically distinct groups. A subset of soft tissue ME tumors with clear cell morphology harbor an EWSR1-POU5F1 fusion, which can be used as a molecular diagnostic test in difficult cases. These findings do not support a pathogenetic relationship between soft tissue ME tumors and their salivary gland counterparts.
Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2011
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 ... more This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
Cytogenetics has long represented a critical component in the clinical evaluation of hematologic ... more Cytogenetics has long represented a critical component in the clinical evaluation of hematologic malignancies. Chromosome banding studies provide a simultaneous snapshot of genome-wide copy number and structural variation, which have been shown to drive tumorigenesis, define diseases, and guide treatment. Technological innovations in sequencing have ushered in our present-day clinical genomics era. With recent publications highlighting novel sequencing technologies as alternatives to conventional cytogenetic approaches, we, an international consortium of laboratory geneticists, pathologists, and oncologists, describe herein the advantages and limitations of both conventional chromosome banding and novel sequencing technologies and share our considerations on crucial next steps to implement these novel technologies in the global clinical setting for a more accurate cytogenetic evaluation, which may provide improved diagnosis and treatment management. Considering the clinical, logisti...
The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a col... more The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter appr...
BCR-ABL1 kinase inhibitors have improved the prognosis of Philadelphia-chromosome-positive (Ph+)-... more BCR-ABL1 kinase inhibitors have improved the prognosis of Philadelphia-chromosome-positive (Ph+)-acute lymphoblastic leukemia (ALL). Ph-like (or BCR-ABL1-like) ALL does not express BCR-ABL1 but commonly harbors other genomic alterations of signaling molecules that may be amenable to therapy. Here, we report a case with a NUP214-ABL1 fusion detected at relapse by multiplexed, targeted RNA sequencing. It had escaped conventional molecular work-up at diagnosis, including cytogenetic analysis and fluorescence in situ hybridization for ABL1 rearrangements. The patient had responded poorly to initial multi-agent chemotherapy and inotuzumab immunotherapy at relapse before the fusion was revealed. The addition of dasatinib targeting NUP214-ABL1 to inotuzumab resulted in complete molecular remission, but recurrence occurred rapidly with dasatinib alone. However, deep molecular remission was recaptured with a combination of blinatumomab and ponatinib, so he could proceed to allotransplantatio...
Key Points Targeted RNA sequencing detected a cryptic G3BP1-PDGFRB rearrangement in a myeloid neo... more Key Points Targeted RNA sequencing detected a cryptic G3BP1-PDGFRB rearrangement in a myeloid neoplasm with eosinophilia and normal FISH studies. Consistent with the patient’s response to imatinib, we demonstrate this rearrangement is oncogenic and sensitive to TKI in cell culture.
Cytologic and cytogenetic results obtained from patients fulfilling the FAB criteria for the diag... more Cytologic and cytogenetic results obtained from patients fulfilling the FAB criteria for the diagnosis of acute nonlymphocytic leukemia (ANLL) of megakaryocytic lineage (ANLL-M7) are reported. Eleven cases were de novo ANLL-M7, of whom three presented with acute myelofibrosis. Four cases were megakaryoblastic transformations of chronic myelogenous leukemia (two cases), refractory anemia with excess of blasts (one case), and polycythemia vera (one case). Four patients showed a minority of granular blasts, with occasional Auer rods in one. Positive myeloperoxidase and/or sudan black-B stainings and CD13 positivity in these cases were consistent with the presence of a myeloid involvement. Morphologic evidence of associated myelodysplastic features was detected in all evaluable patients with de novo ANLL-M7. These cytologic findings indicate that ANLL-M7 may frequently represent a multilineage proliferation. Cytogenetic studies revealed -7/7q- and +8, alone or in combination with additi...
This article (1) has been retracted at the request of the editors. The editors were made aware of... more This article (1) has been retracted at the request of the editors. The editors were made aware of concerns regarding potential manipulation of data in the article. An internal review by the editors determined that multiple Gapdh bands appear to be duplicated in Fig. 3A. In addition, the same g-tubulin Western blot band appears to be duplicated multiple times in Fig. 3B. The authors were not able to provide the original data to dispel these concerns.
Eighty-eight endometrial specimens from 36 postmenopausal breast cancer patients treated with tam... more Eighty-eight endometrial specimens from 36 postmenopausal breast cancer patients treated with tamoxifen were investigated cytogenetically and molecularly using fluorescence in situ hybridization with appropriate probes for the HMGIC and HMGIY genes. Twenty control specimens, 10 endometrial polyps, and 10 endometrial biopsy specimens were investigated in the same way. Of the 88 specimens, 44 were from endometrial polyps; 3 were from endocervical polyps; 7 were from cystic endometrium; 30 were from normal or atrophic endometrium, normal endocervix, or myometrium; and 4 were from endometrial carcinomas. Chromosome investigation of the endometrial polyps showed the nature of the chromosome changes in tamoxifen-induced polyps to be the same as that in the controls and in sporadic endometrial polyps described in the literature. HMGIC and HMGIY gene rearrangements in both groups were identical as shown by fluorescence in situ hybridization, which also allowed for the detection of seven hid...
Next generation sequencing (NGS) is increasingly being used clinically to characterize the molecu... more Next generation sequencing (NGS) is increasingly being used clinically to characterize the molecular alterations found in patients' tumors. These testing results have the potential to affect clinical care by guiding therapeutic approaches based upon genotype. NGS based testing approaches have a distinct advantage over provider-ordered single gene testing in that they can detect unexpected, yet clinically important genetic changes. Here, we illustrate this principle with the case of a 33-year-old man with myeloid sarcoma that was refractory to six different chemotherapeutic regimens. Our clinical NGS assay detected an unanticipated FIP1L1-PDGFRA rearrangement in his tumor. The patient was immediately placed on Imatinib therapy to which he responded, and remains in remission 10 months after the rearrangement was initially detected.
Klinefelter syndrome (KS), a 47,XXY chromosomal abnormality, has been shown to be associated with... more Klinefelter syndrome (KS), a 47,XXY chromosomal abnormality, has been shown to be associated with a number of malignancies, but has not been linked to acute leukemias to date. We present a case of a 54-year-old male diagnosed with acute myeloid leukemia (AML) with monocytic differentiation, whose cytogenetic and subsequent FISH analyses revealed a constitutional 47,XXY karyotype. We also review and discuss relevant prior literature.
Dermatofibrosarcoma protuberans (DFSP) and giant cell fibroblastoma (GCF) are recurrent, infiltra... more Dermatofibrosarcoma protuberans (DFSP) and giant cell fibroblastoma (GCF) are recurrent, infiltrative skin tumors that presently are treated with surgery. DFSP and GCF tumors are genetically characterized by chromosomal rearrangements fusing the collagen type Ialpha1 (COLIA1) gene to the platelet-derived growth factor B-chain (PDGFB) gene. It has been shown that the resulting COL1A1/PDGF-B fusion protein is processed to mature PDGF-BB. Autocrine PDGF receptor stimulation has therefore been predicted to contribute to DFSP and GCF tumor development and growth. Here we demonstrate presence of activated PDGF receptors in primary cultures derived from six different DFSP and GCF tumors. Three of the primary cultures were further characterized; their in vitro growth displayed an increased sensitivity to treatment with the PDGF receptor tyrosine kinase inhibitor STI571, as compared with normal fibroblasts. Transplantable tumors, displaying a DFSP-like histology, were established from one of...
Aberrations of the HMGIC gene, encoding an architectural transcription factor and located in the ... more Aberrations of the HMGIC gene, encoding an architectural transcription factor and located in the chromosomal region 12q15, are very frequent among benign mesenchymal tumors, such as lipomas, uterine leiomyomas, or pulmonary chondroid hamartomas. These HMGIC aberrations are caused by characteristic structural chromosomal aberrations, either visible by conventional cytogenetics or as cryptic abnormalities. Some of these aberrations of chromosome 12 are not specific for particular tumor entities but can occur in a variety of tumors with HMGIC abnormalities. One such example is the pericentric inversion inv(12)(p11.2q15). Starting from the ectopic sequence derived from an HMGIC fusion transcript of an aggressive angiomyxoma with such an inversion we established three PAC clones covering the breakpoint region 12p11 and cloned part of a yet unknown gene in 12p11.2, which is fused to the third exon of HMGIC. Using fluorescence in situ hybridization with these PACs we were able to show that...
Proceedings of the National Academy of Sciences, 2001
Endometrial stromal tumors are divided into three types: benign stromal nodules, endometrial stro... more Endometrial stromal tumors are divided into three types: benign stromal nodules, endometrial stromal sarcomas, and undifferentiated endometrial sarcomas. A variety of cytogenetic abnormalities involving chromosome 7 have been reported in endometrial stromal sarcomas, including a recurrent t(7;17)(p15;q21). We have identified two zinc finger genes, which we have termed JAZF1 and JJAZ1 , at the sites of the 7p15 and 17q21 breakpoints. Analyses of tumor RNA indicate that a JAZF1 / JJAZ1 fusion is present in all types of endometrial stromal tumors; however, the fusion appears to be rarer among endometrial stromal sarcomas that would be considered high-grade according to certain classification schemes. These findings suggest that the less malignant endometrial stromal tumors may evolve toward more malignant types, but that some endometrial stromal sarcomas with relatively abundant mitotic activity may compose a biologically distinct group.
Proceedings of the National Academy of Sciences, 2009
The prognosis for adults with precursor B-cell acute lymphoblastic leukemia (B-ALL) remains poor,... more The prognosis for adults with precursor B-cell acute lymphoblastic leukemia (B-ALL) remains poor, in part from a lack of therapeutic targets. We identified the type I cytokine receptor subunit CRLF2 in a functional screen for B-ALL–derived mRNA transcripts that can substitute for IL3 signaling. We demonstrate that CRLF2 is overexpressed in approximately 15% of adult and high-risk pediatric B-ALL that lackMLL, TCF3, TEL,andBCR/ABLrearrangements, but not in B-ALL with these rearrangements or other lymphoid malignancies. CRLF2 overexpression can result from translocation with theIGHlocus or intrachromosomal deletion and is associated with poor outcome. CRLF2 overexpressing B-ALLs share a transcriptional signature that significantly overlaps with a BCR/ABL signature, and is enriched for genes involved in cytokine receptor and JAK-STAT signaling. In a subset of cases, CRLF2 harbors a Phe232Cys gain-of-function mutation that promotes constitutive dimerization and cytokine independent grow...
Aneurysmal bone cysts (ABC) are locally aggressive bone tumors that often feature chromosome 17p1... more Aneurysmal bone cysts (ABC) are locally aggressive bone tumors that often feature chromosome 17p13 rearrangements. One of the ABC 17p13 rearrangementst(16;17)(q22;p13)-was recently shown to create a CDH11-USP6 fusion in which the USP6/TRE17 oncogene is overexpressed through juxtaposition with the CDH11 promoter. Herein, we characterize four different ABC translocations involving 17p13, and we show that each is associated with a novel USP6 fusion oncogene. Specifically, we demonstrate that t(1;17), t(3;17), t(9;17), and t(17;17) result in USP6 fusions with TRAP150 (thyroid receptor-associated protein 150), ZNF9 (ZiNc Finger 9), Osteomodulin, and COL1A1 (Collagen 1A1), respectively. The oncogenic mechanism in these fusion genes is akin to CDH11-USP6, with the USP6 coding sequences juxtaposed to the promoter regions in each of the four novel translocation partners. The novel fusion partners appear well suited to drive USP6 transcription in the bone/ mesenchymal context: osteomodulin is expressed strongly in osteoblastic lineages, and the COL1A1 promoter has an oncogenic role in the mesenchymal cancer dermatofibrosarcoma protuberans. In summary, these studies show that USP6 oncogenic activation results from heterogeneous genomic mechanisms involving USP6 transcriptional upregulation by juxtaposition with ectopic promoters.
Apart from its hormone responsiveness, little about the pathobiology of intravenous leiomyomatosi... more Apart from its hormone responsiveness, little about the pathobiology of intravenous leiomyomatosis (IVL), a rare smooth muscle proliferation, is known. We investigated the cytogenetics and molecular biology of IVL in a 40-year-old female who presented with an abrupt onset of dyspnea. In addition to the intracaval tumor mass composed of histologically benign smooth muscle, four distinct retroperitoneal "fibroids" were cytogenetically investigated. An identical abnormal karyotype, 45,XX,der(14)t(12;14)(q15;q24),-22, was observed in all five specimens. Fluorescence in situ hybridization revealed three copies of HMGIC (alias HMGA2), two on the normal chromosomes 12 at 12q15, as well as another on the der(14) in the breakpoint region, suggesting that the 12q breakpoint occurred 5' (centromeric) to HMGIC (HMGA2), as has been frequently observed in uterine leiomyoma. Such similarity in chromosomal rearrangements suggests that there may be a pathogenetic relationship between IVL and uterine leiomyomata with t(12;14). Skewed X inactivation was observed in each tumor sample, but not in the myometrium. In each tumor, the lower molecular weight allele of HUMARA was nonrandomly inactivated. This pattern of X inactivation is most consistent with origin from a single transformation event, and in this regard, IVL more closely resembles disseminated peritoneal leiomyomatosis than typical uterine leiomyomata.
Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely t... more Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing transdifferentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.
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