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1.
Mod Pathol ; 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35504958

RESUMO

EZH2 coding mutation (EZH2MUT), resulting in loss-of-function, is an independent predictor of overall survival in MDS. EZH2 function can be altered by other mechanisms including copy number changes, and mutations in other genes and non-coding regions of EZH2. Assessment of EZH2 protein can identify alterations of EZH2 function missed by mutation assessment alone. Precise evaluation of EZH2 function and gene-protein correlation in clinical MDS cohorts is important in the context of upcoming targeted therapies aimed to restore EZH2 function. In this study, we evaluated the clinicopathologic characteristics of newly diagnosed MDS patients with EZH2MUT and correlated the findings with protein expression using immunohistochemistry. There were 40 (~6%) EZH2MUT MDS [33 men, seven women; median age 74 years (range, 55-90)]. EZH2 mutations spanned the entire coding region. Majority had dominant EZH2 clone [median VAF, 30% (1-92)], frequently co-occurring with co-dominant TET2 (38%) and sub-clonal ASXL1 (55%) and RUNX1 (43%) mutations. EZH2MUT MDS showed frequent loss-of-expression compared to EZH2WT (69% vs. 27%, p = 0.001). Interestingly, NINE (23%) EZH2WT MDS also showed loss-of-expression. EZH2MUT and loss-of-expression significantly associated with male predominance and chr(7) loss. Further, only EZH2 loss-of-expression patients showed significantly lower platelet counts, a trend for higher BM blast% and R-IPSS scores. Over a 14-month median follow-up, both EZH2MUT (p = 0.027) and loss-of-expression (p = 0.0063) correlated with poor survival, independent of R-IPSS, age and gender. When analyzed together, loss-of-expression showed a stronger correlation than mutation (p = 0.061 vs. p = 0.43). In conclusion, immunohistochemical assessment of EZH2 protein, alongside mutation, is important for prognostic workup of MDS.

3.
Ann Diagn Pathol ; 59: 151951, 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35489185

RESUMO

The development of clonally related hematologic neoplasms in the setting of primary mediastinal germ cell tumors (PMGCTs) has been recognized previously and is associated with a dismal prognosis. However, the presentation of hematologic neoplasms as chronic myelomonocytic leukemia (CMML) and hemophagocytic lymphohistiocytosis (HLH) has been rarely reported. Here we report two patients with PMGCTs and hematologic neoplasms. The PMGCT was composed mostly of yolk sac tumor whereas the hematologic neoplasms had morphologic features that resembled CMML and HLH. The hematologic neoplasms from both patients harbored isochromosome 12p [i(12p)] and TP53 mutations, supporting a clonal relationship between these tumors. This association represents a unique clinical syndrome that likely contributes to the poor clinical outcome of these patients.

4.
Appl Spectrosc ; 76(4): 508-518, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35236126

RESUMO

Collagen quantity and integrity play an important role in understanding diseases such as myelofibrosis (MF). Label-free mid-infrared spectroscopic imaging (MIRSI) has the potential to quantify collagen while minimizing the subjective variance observed with conventional histopathology. Infrared (IR) spectroscopy with polarization sensitivity provides chemical information while also estimating tissue dichroism. This can potentially aid MF grading by revealing the structure and orientation of collagen fibers. Simultaneous measurement of collagen structure and biochemical properties can translate clinically into improved diagnosis and enhance our understanding of disease progression. In this paper, we present the first report of polarization-dependent spectroscopic variations in collagen from human bone marrow samples. We build on prior work with animal models and extend it to human clinical biopsies with a practical method for high-resolution chemical and structural imaging of bone marrow on clinical glass slides. This is done using a new polarization-sensitive photothermal mid-infrared spectroscopic imaging scheme that enables sample and source independent polarization control. This technology provides 0.5 µm spatial resolution, enabling the identification of thin (≈1 µm) collagen fibers that were not separable using Fourier Transform Infrared (FT-IR) imaging in the fingerprint region at diffraction-limited resolution ( ≈ 5 µm). Finally, we propose quantitative metrics to identify fiber orientation from discrete band images (amide I and amide II) measured under three polarizations. Previous studies have used a pair of orthogonal polarization measurements, which is insufficient for clinical samples since human bone biopsies contain collagen fibers with multiple orientations. Here, we address this challenge and demonstrate that three polarization measurements are necessary to resolve orientation ambiguity in clinical bone marrow samples. This is also the first study to demonstrate the ability to spectroscopically identify thin collagen fibers (≈1 µm diameter) and their orientations, which is critical for accurate grading of human bone marrow fibrosis.


Assuntos
Medula Óssea , Colágeno , Amidas , Animais , Medula Óssea/diagnóstico por imagem , Colágeno/química , Humanos , Espectrofotometria Infravermelho , Espectroscopia de Infravermelho com Transformada de Fourier/métodos
5.
Signal Transduct Target Ther ; 7(1): 51, 2022 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-35185150

RESUMO

Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2-selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN, and identified the activation of RAS/MAPK pathway, leading to increased stability and higher levels of MCL-1 protein, as a major acquired mechanism of VEN resistance. MCL-1 sustained survival and maintained mitochondrial respiration in VEN-RE cells, which had impaired electron transport chain (ETC) complex II activity, and MCL-1 silencing or pharmacologic inhibition restored VEN sensitivity. In support of the importance of RAS/MAPK activation, we found by single-cell DNA sequencing rapid clonal selection of RAS-mutated clones in AML patients treated with VEN-containing regimens. In summary, these findings establish RAS/MAPK/MCL-1 and mitochondrial fitness as key survival mechanisms of VEN-RE AML and provide the rationale for combinatorial strategies effectively targeting these pathways.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Sistema de Sinalização das MAP Quinases , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas Proto-Oncogênicas c-bcl-2 , Sulfonamidas , Proteínas ras , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/farmacologia
6.
Mod Pathol ; 35(3): 419-426, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34608246

RESUMO

The 2016 WHO classification introduced the category of high-grade B-cell lymphoma (HGBL), which includes one poorly understood subset, blastoid-HGBL. Establishing the diagnosis and distinguishing blastoid-HGBL from B-acute lymphoblastic leukemia (B-ALL) in bone marrow can be challenging. We assessed 31 cases of blastoid-HGBL diagnosed initially in bone marrow and compared this group to 36 cases of B-ALL using immunophenotyping, fluorescence in situ hybridization, and targeted next generation sequencing analysis. The 31 blastoid-HGBL cases included 14 HGBL with MYC and BCL2 and/or BCL6 rearrangements (double hit lymphoma, DHL), 13 HGBL, not otherwise specified (NOS), and four cases with TdT expression that were difficult to classify. Compared with B-ALL, blastoid-HGBL cases more often showed increased intensity/bright expression of CD20, CD38, CD45, BCL-6, and MYC, and less frequent bright expression of CD10 and TdT. Cases of blastoid-HGBL also more frequently had MYC rearrangement, a complex karyotype and TP53 mutation (p < 0.01). With the exception of CD34, no other single factor, including TdT, was sensitive or adequately specific to distinguish blastoid-HGBL from B-ALL. We developed a scoring system using six distinctive features between 16 cases of unequivocal blastoid HGBL and 22 cases of CD34-positive B-ALL, with a score of ≥3 defining blastoid-HGBL. The system was further validated by using 15 cases of surface light chain negative, and/or CD45 dim to negative blastoid-HGBL and 14 cases of CD34-negative B-ALL. The sensitivity, specificity, positive, and negative predictive value of this scoring system were 100%, 94%, 94%, and 100%, respectively. Using this system, the four cases with TdT expression were all classified as blastoid-HGBL: three were DHL and one was HGBL-NOS. In conclusion, blastoid-HGBL shows distinctive immunophenotypic, cytogenetic, and molecular features as compared with B-ALL. The proposed scoring system can be helpful for the classification of diagnostically challenging blastoid lymphoid tumors presenting initially in the bone marrow.


Assuntos
Linfoma de Burkitt , Linfoma de Células B , Linfoma Difuso de Grandes Células B , Medula Óssea/patologia , Linfoma de Burkitt/genética , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética
7.
Ann Diagn Pathol ; 56: 151860, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34823075

RESUMO

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with myelofibrosis (MF). Bone marrow (BM) morphologic evaluation of myelofibrosis following allo-HSCT is known to be challenging in this context because resolution of morphologic changes is a gradual process. PATIENTS AND METHODS: We compared BM samples of patients with myelofibrosis who underwent first allo-HSCT and achieved molecular remission by day 100 with BM samples of patients who continued to have persistent molecular evidence of disease following allo-HSCT. RESULTS: The study group included 29 patients: 17 primary MF, 7 post-polycythemia vera (PV) MF, and 5 post-essential thrombocythemia (ET) MF. In this cohort there were 18 JAK2 p.V617F, 8 CALR; 1 MPL, and 2 patients had concurrent JAK2 p.V617F and MPL mutations. The control group included 5 patients with primary MF, one with post-PV MF, one with post-ET MF (5 JAK2 p.V617F; 2 CALR). Following allo-HSCT, both groups showed reduction in BM cellularity and number of megakaryocytes. The study cohort also less commonly had dense megakaryocyte clusters and endosteal located megakaryocytes and showed less fibrosis. There was no statistical difference in BM cellularity, presence of erythroid islands, degree of osteosclerosis, or megakaryocyte number, size, nuclear lobation, presence of clusters or intrasinusoidal location. CONCLUSIONS: Following allo-HSCT at 100 days, morphologic evaluation of BM in patients with MF cannot reliably predict persistence versus clearance of molecular evidence of MF. Disappearance of BM MF, dense megakaryocyte clusters, and endosteal localization of megakaryocytes are suggestive of disease response.


Assuntos
Medula Óssea/patologia , Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária/patologia , Adulto , Idoso , Feminino , Humanos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/genética , Mielofibrose Primária/terapia , Resultado do Tratamento
8.
Blood Adv ; 5(16): 3163-3173, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34424319

RESUMO

Outcomes in patients with high-risk and treatment-resistant myelofibrosis (MF) post-JAK inhibitor therapy remain poor, with no approved drug therapies beyond the JAK inhibitor class. In certain clinical situations, such as severe thrombocytopenia, administration of most JAK inhibitors are contraindicated. Thus, there is an unmet medical need for the development of novel agents for patients with MF. SMAC mimetics [or inhibitor of apoptosis (IAP) antagonists] induce apoptosis in cancer cells. Because these agents are hypothesized to have increased activity in a tumor necrosis factor-α cytokine-rich microenvironment, as is the case with MF, we conducted a single-center, investigator-initiated phase 2 clinical trial, with a monovalent SMAC mimetic LCL161 (oral, starting dose, 1500 mg per week) in patients with intermediate to high-risk MF. In an older group, 66% with ≥2 prior therapies and a median baseline platelet count of 52 × 103/µL and 28% with ASXL1 mutations, we observed a 30% objective response by Revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria. Notably, 6 responding patients achieved clinical improvement of anemia: 4, hemoglobin response; 2, transfusion independence. Median OS was 34 months (range, 2.2-60.1+). Reductions of cIAPs were observed in all responders. The most common toxicity was nausea/vomiting (N/V) in 64% (mostly grade 1/2); fatigue in 46%; and dizziness/vertigo in 30%. There were 4 grade 3/4 adverse events (2, syncope; 1, N/V; 1, skin eruption/pruritis). There were 2 deaths during the study period, both unrelated to the study drug. SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161.


Assuntos
Transtornos Mieloproliferativos , Mielofibrose Primária , Apoptose , Humanos , Mielofibrose Primária/tratamento farmacológico , Tiazóis
9.
Mod Pathol ; 34(12): 2148-2153, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34155351

RESUMO

Breast implant-associated anaplastic large cell lymphoma (ALCL) is a distinctive type of T-cell lymphoma that arises around textured-surface breast implants. In a subset of patients, this disease can involve surrounding tissues, spread to regional lymph nodes, and rarely metastasize to distant sites. The aim of this study was to assess sequential pathologic specimens from patients with breast implant-associated ALCL to better understand the natural history of early-stage disease. To achieve this goal, we searched our files for patients who had breast implant-associated ALCL and who had undergone earlier surgical intervention with assessment of biopsy or cytologic specimens. We then focused on the patient subset in whom a definitive diagnosis was not established, and patients did not receive current standard-of-care therapy at that time. We identified a study group of ten patients with breast implant-associated ALCL in whom pathologic specimens were collected 0.5 to 4 years before a definitive diagnosis was established. A comparison of these serial biopsy specimens showed persistent disease without change in pathologic stage in three patients, progression in five patients, and persistence versus progression in two patients. Eventually, six patients underwent implant removal with complete capsulectomy and four underwent partial capsulectomy. Seven patients also received chemotherapy because of invasive disease, three of whom also received radiation therapy, two brentuximab vedotin after chemotherapy failure, and one allogeneic stem cell transplant. Eight patients achieved complete remission and two had partial remission after definitive therapy. At time of last follow-up, six patients were alive without disease, one had evidence of disease, one died of disease, and two patients died of unrelated cancers. In summary, this analysis of sequential specimens from patients with breast implant-associated ALCL suggests these neoplasms persist or progress over time if not treated with standard-of-care therapy.


Assuntos
Implante Mamário/efeitos adversos , Implantes de Mama/efeitos adversos , Linfoma Anaplásico de Células Grandes/patologia , Biópsia , Implante Mamário/instrumentação , Implante Mamário/mortalidade , Progressão da Doença , Feminino , Humanos , Linfoma Anaplásico de Células Grandes/etiologia , Linfoma Anaplásico de Células Grandes/mortalidade , Linfoma Anaplásico de Células Grandes/terapia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Desenho de Prótese , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Propriedades de Superfície , Fatores de Tempo , Resultado do Tratamento
11.
Mod Pathol ; 34(9): 1673-1685, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33990705

RESUMO

Myeloid/lymphoid neoplasms (M/LN) with 13q12/FLT3 rearrangement have been suggested as candidates for possible inclusion in the World Health Organization classification group of M/LN with eosinophilia (M/LN-eo). We report 12 patients with confirmed FLT3 rearrangement, six with t(12;13)/ETV6-FLT3; one with ins(13;22)/BCR-FLT3; and five with an unconfirmed partner gene located on chromosome bands 2p16, 3q27, 5q15, 5q35, and 7q36. Disease presentations were heterogeneous, including lymphoblastic leukemia/lymphoma, myeloid sarcoma, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndrome. However, some common features were observed, such as extramedullary involvement (n = 7, 58%), associated eosinophilia in blood, bone marrow, or tissue (n = 8, 67%), multilineage involvement, either as biphasic myeloid/lymphoid neoplasms (n = 2) or mixed phenotype acute leukemia (n = 2). Mutations were detected in 4/8 (50%) patients by next-generation sequencing. None (0/10) had FLT3 or KIT mutations. Eleven patients received disease-based chemotherapy or hypomethylating agents, three received FLT3 inhibitors, and five patients proceeded to hematopoietic stem cell transplant. Together with a review of 16 cases published in the literature, it is apparent that M/LNs with FLT3 rearrangement show disease features reminiscent of members in the category of M/LN-eo with PDGFRA, PDGFRB, FGFR1, and PCM1/JAK2 rearrangement, characterized by a specific gene rearrangement, frequent eosinophilia, multi-lineage involvement and therapeutic benefit from kinase inhibitors.


Assuntos
Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Pré-Escolar , Feminino , Rearranjo Gênico , Humanos , Masculino , Pessoa de Meia-Idade , Fusão Oncogênica , Adulto Jovem
13.
Cytometry B Clin Cytom ; 100(3): 352-360, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32157815

RESUMO

BACKGROUND: Lymphocytic variant of hypereosinophilic syndrome (L-HES) is a subtype of HES driven by cytokines produced by clonal T-cells. Due to the rarity of its occurrence and challenges in diagnosis, this subtype of HES is under recognized. METHODS AND RESULTS: We report seven patients with L-HES, diagnosed from a group of 136 patients who were referred to our institution for the work-up of hypereosinophilia. The clinical presentation, symptoms and signs were heterogeneous and uncharacteristic; indistinguishable from idiopathic HES. Flow cytometry immunophenotypic analysis revealed aberrant T-cells in all patients, with a Th2 immunophenotype, CD2 + CD3-CD4 + CD5 + CD7dim+/-CD8- in six of seven (86%) cases. CD10 was partially expressed in one of seven (14%) cases, and clonal TCR gene rearrangement was detected by PCR in five of seven (71%) patients. All patients were treated with corticosteroids and two of seven (29%) patients received anti-IL5 antibody therapy. With a median follow-up time of 7.5 years (2.3-14.1 years), one (11%) patient developed peripheral T-cell lymphoma 6.1 years after the initial diagnosis of L-HES and responded well to chemotherapy. All patients were alive at the last follow-up. CONCLUSION: In conclusion, a combination of flow cytometry immunophenotyping and molecular analysis allows the identification of aberrant T-cells, facilitating a diagnosis of L-HES in patients with eosinophilia. A correct diagnosis is essential for the proper management of these patients.


Assuntos
Síndrome Hipereosinofílica/diagnóstico , Síndrome Hipereosinofílica/patologia , Linfócitos T/patologia , Adulto , Idoso , Citocinas/metabolismo , Feminino , Citometria de Fluxo/métodos , Humanos , Síndrome Hipereosinofílica/metabolismo , Imunofenotipagem/métodos , Masculino , Pessoa de Meia-Idade , Linfócitos T/metabolismo
14.
Mod Pathol ; 34(1): 20-31, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32694616

RESUMO

JAK2, CALR, and MPL are myeloproliferative neoplasm (MPN)-driver mutations, whereas SF3B1 is strongly associated with ring sideroblasts (RS) in myelodysplastic syndrome (MDS). Concomitant mutations of SF3B1 and MPN-driver mutations out of the context of MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T) are not well-studied. From the cases (<5% blasts) tested by NGS panels interrogating at least 42 myeloid neoplasm-related genes, we identified 18 MDS/MPN-RS-T, 42 MPN, 10 MDS, and 6 MDS/MPN-U cases with an SF3B1 and an MPN-driver mutation. Using a 10% VAF difference to define "SF3B1-dominant," "MPN-mutation dominant," and "no dominance," the majority of MDS/MPN-RS-T clustered in "SF3B1-dominant" and "no dominance" regions. Aside from parameters as thrombocytosis and ≥15% RS required for RS-T, MDS also differed in frequent neutropenia, multilineage dysplasia, and notably more cases with <10% VAF of MPN-driver mutations (60%, p = 0.0346); MPN differed in more frequent splenomegaly, myelofibrosis, and higher VAF of "MPN-driver mutations." "Gray zone" cases with features overlapping MDS/MPN-RS-T were observed in over one-thirds of non-RS-T cases. This study shows that concomitant SF3B1 and MPN-driver mutations can be observed in MDS, MPN, and MDS/MPN-U, each showing overlapping but also distinctively different clinicopathological features. Clonal hierarchy, cytogenetic abnormalities, and additional somatic mutations may in part contribute to different disease phenotypes, which may help in the classification of "gray zone" cases.


Assuntos
Calreticulina/genética , Janus Quinase 2/genética , Doenças Mieloproliferativas-Mielodisplásicas/genética , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Receptores de Trombopoetina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
16.
Nat Commun ; 11(1): 5327, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087716

RESUMO

Clonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Precise characterization of clonal architecture is essential to understand the evolutionary history of tumor development and its association with treatment resistance. Here, using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. The single-cell data reveals cell-level mutation co-occurrence and enables reconstruction of mutational histories characterized by linear and branching patterns of clonal evolution, with the latter including convergent evolution. Through xenotransplantion, we show leukemia initiating capabilities of individual subclones evolving in parallel. Also, by simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Lastly, single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine.


Assuntos
Evolução Clonal/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Idoso , Animais , Evolução Clonal/efeitos dos fármacos , Estudos de Coortes , Feminino , Estudos de Associação Genética , Genômica , Xenoenxertos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Modelos Genéticos , Mutação , Análise de Sequência de DNA , Análise de Célula Única
17.
J Natl Compr Canc Netw ; 18(10): 1300-1304, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33022638

RESUMO

RNA-seq was used to identify the partner gene and confirm the presence of a BCR-PDGFRB fusion. Identification of this fusion product resulted in successful treatment and long-term remission of this myeloid neoplasm. Based on our results, we suggest that despite current WHO recommendations, screening for PDGFRB rearrangement in cases of leukocytosis with eosinophilia and no other etiologic explanation is necessary, even if the karyotype is normal.


Assuntos
Eosinofilia , Transtornos Mieloproliferativos , Neoplasias , Proteínas de Fusão Oncogênica/genética , Eosinofilia/diagnóstico , Eosinofilia/genética , Humanos , Mesilato de Imatinib , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Neoplasias/diagnóstico , Neoplasias/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Translocação Genética
18.
Eur J Haematol ; 105(4): 449-459, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32535947

RESUMO

OBJECTIVES: It has been believed that immunoglobulins can only be produced by B lymphocytes and plasma cells. We have previously reported that IgG can be expressed in myeloblasts from patients with acute myeloid leukemia (AML) and plays a role in the proliferation and apoptosis of leukemic cells. However, its clinical impact has not been assessed. METHODS: We assessed the expression of different classes of immunoglobulin in peripheral blood and bone marrow samples from 132 AML patients and correlated the levels of expression with clinicopathologic and molecular genetic features, as well as clinical outcome. RESULTS: We found that, in addition to IgG, all classes of immunoglobulin are expressed in myeloblasts, including IgG, IgM, IgA, IgD, IgE, Igκ, and Igλ. The levels of IgG expression (coupled with Igκ or Igλ) are higher than those of IgM, IgA, IgD, and IgE. Using receiver operating characteristic (ROC) curve analysis, we identified two distinct groups of AML patients with differential expression of immunoglobulin and different clinical outcomes. CONCLUSIONS: High levels of immunoglobulin expression are associated with monocytic differentiation, multilineage dysplasia, TET2 and KRAS mutations, and poor overall survival. Assessment of immunoglobulin may serve as a useful marker for prognostic stratification and target therapy.


Assuntos
Regulação Leucêmica da Expressão Gênica , Imunoglobulinas/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Biomarcadores Tumorais , Gerenciamento Clínico , Feminino , Humanos , Isotipos de Imunoglobulinas/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Masculino , Terapia de Alvo Molecular , Mutação , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Curva ROC
20.
Mod Pathol ; 33(9): 1678-1689, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32238878

RESUMO

We studied the characteristics of the provisional category de novo acute myeloid leukemia (AML) with mutated RUNX1 (AML-RUNX1mut) proposed by the World Health Organization (WHO). Until now, most published studies have combined de novo and secondary AML-RUNX1mut. We compared the clinicopathologic characteristics and outcomes of WHO-defined de novo AML-RUNX1mut with de novo AML without RUNX1 alterations (AML-RUNX1wt). We performed sequential NGS to assess RUNX1 mutation stability over disease course. We identified 46 de novo AML-RUNX1mut patients [32 (70%) men, 14 (30%) women; median age, 66.5 years] with 54 RUNX1 mutations [median VAF, 32% (2-97%)]. Point mutations clustered within the runt-homology-domain and frame-shift mutations within the transactivation domain. Compared with AML-RUNX1wt, AML-RUNX1mut showed male predominance (p = 0.02), higher frequency of SRSF2 (p = 0.02), and ASXL1 (p = 0.0004) mutations and normal karyotype (p = 0.01), and absent NPM1 mutations (p = 0.0002). De novo AML-RUNX1mut showed no significant difference in overall survival (OS) compared with AML-RUNX1wt (median: 26 vs. 32 months) (p = 0.71). AML-RUNX1mut with clonal RUNX1 mutation (≥20% VAF) had shorter OS than subclonal <20% VAF (23 months vs. undefined; p = 0.04). However, the difference was not significant when compared with AML-RUNX1wt (23 vs. 32 months; p = 0.23). No significant OS difference was noted between de novo AML-RUNX1mut and AML-NOS-RUNX1wt. By sequential multigene mutation profiling, RUNX1 mutation disappeared at relapse in one of ten patients. Overall, the findings support separate categorization of this entity. However, there is no significant outcome difference compared with AML-RUNX1wt.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Idoso , Linhagem Celular , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Organização Mundial da Saúde
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