Jason Kurzer

All Publications

• Clinicopathologic and Molecular Analysis of Normal Karyotype Therapy-related and De Novo Acute Myeloid Leukemia: A Multi-institutional Study by the Bone Marrow Pathology Group Cantu, M., Kanagal-Shamanna, R., Bueso-Ramos, C., Patel, S., Geyer, J., Tam, W., Li, P., George, T., Nichols, M., Rogers, H., Liu, Y., Aggarwal, N., Kurzer, J., Maracaja, D., Hsi, E., Zaiem, F., Babu, D., Foucar, K., Laczko, D., Bagg, A., Orazi, A., Arber, D., Hasserjian, R., Weinberg, O. SPRINGERNATURE. 2022: 925-927

  View details for Web of Science ID 000770360202202

• Flow Cytometry Forward Scatter as a Predictor of Large Cell Transformation in Follicular Lymphoma: A Retrospective Cyto-Heme Inter-Institutional Collaborative (CHIC) study Menke, J., Wang, L., Xie, Y., Yakubu, R., Balassanian, R., Frank, A., Gupta, S., Kurzer, J., Long, S., Natkunam, Y., Ruiz-Cordero, R., Wen, K., Gratzinger, D. SPRINGERNATURE. 2022: 989-990

  View details for Web of Science ID 000770361802256

• TP53 mutation defines a unique subgroup within complex karyotype de novo and therapy-related MDS/AML. Blood advances Weinberg, O. K., Siddon, A. J., Madanat, Y., Gagan, J., Arber, D. A., Dal Cin, P., Narayanan, D., Ouseph, M. M., Kurzer, J. H., Hasserjian, R. P. 1800

  Abstract

  A subset of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) show complex karyotype (CK), and these cases include a relatively high proportion of cases of therapy-related myeloid neoplasms and TP53 mutations. We aimed to evaluate the clinicopathologic features of outcome of 299 AML and MDS patients with CK. Mutations were present in 287 patients (96%) and the most common mutation detected was in TP53 gene (83%). A higher frequency of TP53 mutations was present in therapy-related cases (p=0.008) with a trend for worse overall survival (OS) in therapy-related patients as compared with de novo (p=0.08) and within the therapy-related group, the presence of TP53 mutation strongly predicted for worse outcome (p=0.0017). However, there was no difference in survival between CK patients based on categorization of AML versus MDS, (p=0.96) or presence of absence of circulating blasts ≥1% (p=0.52). TP53 mutated patients presented with older age (p=0.06) and lower hemoglobin (p=0.004) and marrow blast (p=0.02) compared to those with CK lacking TP53 mutation. Multivariable analysis identified presence of multi-hit TP53 mutation as strongest predictor of worse outcome, while neither a diagnosis of AML versus MDS nor therapy-relatedness independently influenced OS. Our findings suggest that among patients with MDS and AML, the presence of TP53 mutation (in particular multi-hit TP53 mutation) in the context of CK identifies a homogeneously aggressive disease, irrespective of the blast count at presentation or therapy-relatedness. The current classification of these cases into different disease categories artificially separates a single biologic disease entity.

  View details for DOI 10.1182/bloodadvances.2021006239

  View details for PubMedID 35073573

• Evaluation of a measles virus multiplex, triple-target real-time RT-PCR in three specimen matrices at a U.S. academic medical center. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology Broadhurst, M. J., Garamani, N., Hahn, Z., Jiang, B., Weber, J., Huang, C., Sahoo, M. K., Kurzer, J., Hogan, C. A., Pinsky, B. A. 2021; 136: 104757

  Abstract

  BACKGROUND: Measles virus (MeV) is an important cause of acute febrile illness and pediatric mortality globally, with recent U.S. outbreaks associated with under-vaccination. MeV is highly contagious and timely diagnosis is critical to limit spread. RNA detection is the most sensitive method for acute measles diagnosis; however, MeV nucleic acid amplification assays are not widely available.METHODS: We performed a diagnostic accuracy study of a triple-target, real-time RT-PCR (rRT-PCR) assay for simultaneous detection of MeV N, H, and L genes.RESULTS: The MeV triple-target rRT-PCR was tested against serial dilutions (7.0-2.0 log10 copies/mL) of five MeV isolates representing circulating genotypes, and detected 98.7% (74/75) of nasopharyngeal (NP) swab dilutions, 100% (75/75) of plasma dilutions, and 85.3% (64/75) of urine dilutions. MeV RNA detection in urine was markedly improved with the addition of a nucleic acid stabilizing agent. A 95% lower limit of detection (LLOD) of < 3.0 log10 copies/mL was established in each specimen matrix. No cross-reactivity with relevant viruses or interfering substances were identified in specificity studies. The MeV triple-target rRT-PCR detected all three gene targets in a clinical NP swab from an individual with confirmed measles infection. Furthermore, pooled testing from 798 influenza A/B/RSV-negative pediatric NP swabs identified two specimens positive for MeV RNA, confirmed by N gene sequencing to represent shedding of the vaccine-type measles virus.CONCLUSIONS: The MeV triple-target rRT-PCR assay showed high analytic sensitivity across circulating MeV genotypes in three clinically-relevant matrices. Implementation of this assay in the clinical laboratory may facilitate timely diagnosis of acute measles infection and implementation of appropriate infection control interventions.

  View details for DOI 10.1016/j.jcv.2021.104757

  View details for PubMedID 33639409

• Clinical, immunophenotypic and genomic findings of NK lymphoblastic leukemia: a study from the Bone Marrow Pathology Group. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Weinberg, O. K., Chisholm, K. M., Ok, C. Y., Fedoriw, Y., Grzywacz, B., Kurzer, J. H., Mason, E. F., Moser, K. A., Bhattacharya, S., Xu, M., Babu, D., Foucar, K., Tam, W., Bagg, A., Orazi, A., George, T. I., Wang, W., Wang, S. A., Arber, D. A., Hasserjian, R. P. 2021

  Abstract

  Natural killer (NK) cells are lymphocytes of the native immune system that play a pivotal role in host defense and immune surveillance. While the conceptual view of NK-neoplasms is evolving, little is known about the rare NK lymphoblastic leukemia (NK-LL), which remains as a provisional entity in the 2016 WHO Classification. The goal of this study is to characterize NK-LL cases and compare with other CD56 co-expressing acute leukemias. We identified 105 cases, diagnosed as NK-LL (6), CD56+ acute undifferentiated leukemia (AUL) (6), CD56+T-lymphoblastic leukemia (T-LL) (51), and CD56+ acute myeloid leukemia (AML) (42). Compared to AUL patients, NK-LL patients were significantly younger (p=0.021) and presented with higher white blood cell (WBC) (p=0.037) and platelet counts (p=0.041). Flow cytometry showed more frequent expression of cytoplasmic CD3 (cCD3, p=0.064) and CD33, (p=0.065), while HLA-DR was significantly absent from NK-LL (p=0.035) compared to AUL. Compared to T-ALL, NK-LL cases showed less frequent cCD3 (p=0.002), CD4 (p=0.051), and CD10 expression (p=0.06). The frequency of abnormal karyotypes was similar between NK-LL, AUL, and T-ALL. The mutational profile differed in four leukemia groups, with a significance enrichment of NOTCH1 (p=0.002), ETV6 (p=0.002) and JAK3 (p=0.02) mutations in NK-LL as compared to AML. As compared to T-ALL, NK-LL cases showed a higher number of total mutations (p=0.04) and significantly more frequent ETV6 mutations (p=0.004). Clinical outcome data showed differences in overall survival between all four groups (p=0.0175), but no difference in event free survival (p=0.246). In this largest study to date, we find that that NK-LL shows clinical presentation, immunophenotypic and molecular characteristics distinct from AUL, T-ALL, and AML. Our findings suggest NK-LL is a distinct acute leukemia entity and should be considered in the clinical diagnosis of acute leukemias of ambiguous lineage.

  View details for DOI 10.1038/s41379-021-00739-4

  View details for PubMedID 33526873

• Combined SARS-CoV-2 nucleic acid amplification testing and respiratory virus panel RT-PCR on the Hologic Panther Fusion system. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology Stevens, B. A., Hogan, C. A., Mfuh, K. O., Khan, G. n., Sahoo, M. K., Huang, C. n., Garamani, N. n., Zehnder, J. n., Kurzer, J. n., Pinsky, B. A. 2021; 138: 104792

  Abstract

  Significant overlap exists between the symptoms of SARS-CoV-2 and other respiratory viruses. This poses a serious challenge to clinical diagnosis, laboratory testing, and infection control programs.To evaluate the performance of the Hologic Panther Fusion Respiratory Assays (RA) compared to the GenMark ePlex Respiratory Pathogen Panel (RPP) and to assess the ability of the Panther Fusion to perform parallel testing of SARS-CoV-2 and other respiratory viruses from a single sample.A diagnostic comparison study was carried out using 375 clinical nasopharyngeal specimens. Assay performance was assessed by overall, positive, and negative percent agreement and Cohen's kappa coefficient.Overall agreement between the Fusion RA and ePlex RPP was 97.3 % (95 % CI 96.3-98.0), positive percent agreement was 97.2 % (95 % CI 93.0-99.2), negative percent agreement was 97.3 % (95 % CI 96.3-98.0), and the kappa coefficient was 0.85 (95 % CI 0.81-0.89). Forty additional viruses in 30 specimens were detected by Fusion that were not detected by ePlex. The maximum specimen throughput for parallel testing of the Fusion Respiratory Assays with SARS-CoV-2 was 275 samples in 20.7 h for Fusion SARS-CoV-2 and 350 samples in 20.0 h for Aptima Transcription Mediated Amplification SARS-CoV-2.Fusion RA demonstrated substantial agreement compared to the ePlex RPP. However, the Fusion detected respiratory viruses not identified by ePlex, consistent with higher clinical sensitivity. Workflows for parallel testing of respiratory pathogens and SARS-CoV-2 demonstrate that the Panther Fusion instrument provides a flexible, moderate to high throughput testing option for pandemic and seasonal respiratory viruses.

  View details for DOI 10.1016/j.jcv.2021.104792

  View details for PubMedID 33770659

• Nonleukemic T/B mixed phenotype acute leukemia with PHF6 and NOTCH1 mutations. Blood Silva, O., Kurzer, J. 2021; 138 (9): 818

  View details for DOI 10.1182/blood.2021012538

  View details for PubMedID 34473233

• PHF6 Mutations in Hematologic Malignancies. Frontiers in oncology Kurzer, J. H., Weinberg, O. K. 2021; 11: 704471

  Abstract

  Next generation sequencing has uncovered several genes with associated mutations in hematologic malignancies that can serve as potential biomarkers of disease. Keeping abreast of these genes is therefore of paramount importance in the field of hematology. This review focuses on PHF6, a highly conserved epigenetic transcriptional regulator that is important for neurodevelopment and hematopoiesis. PHF6 serves as a tumor suppressor protein, with PHF6 mutations and deletions often implicated in the development of T-lymphoblastic leukemia and less frequently in acute myeloid leukemia and other myeloid neoplasms. PHF6 inactivation appears to be an early event in T-lymphoblastic leukemogenesis, requiring cooperating events, including NOTCH1 mutations or overexpression of TLX1 and TLX3 for full disease development. In contrast, PHF6 mutations tend to occur later in myeloid malignancies, are frequently accompanied by RUNX1 mutations, and are often associated with disease progression. Moreover, PHF6 appears to play a role in lineage plasticity within hematopoietic malignancies, with PHF6 mutations commonly present in mixed phenotype acute leukemias with a predilection for T-lineage marker expression. Due to conflicting data, the prognostic significance of PHF6 mutations remains unclear, with a subset of studies showing no significant difference in outcomes compared to malignancies with wild-type PHF6, and other studies showing inferior outcomes in certain patients with mutated PHF6. Future studies are necessary to elucidate the role PHF6 plays in development of T-lymphoblastic leukemia, progression of myeloid malignancies, and its overall prognostic significance in hematopoietic neoplasms.

  View details for DOI 10.3389/fonc.2021.704471

  View details for PubMedID 34381727

  View details for PubMedCentralID PMC8350393

• Human Germinal Center-associated Lymphoma (HGAL) Is a Reliable Marker of Normal and Neoplastic Follicular Helper T Cells Including Angioimmunoblastic T-Cell Lymphoma. The American journal of surgical pathology Koo, M., Zhang, J., Tan, B., Kurzer, J., Gratzinger, D., Zhao, S., Suarez, C., Lossos, I. S., Warnke, R. A., Natkunam, Y. 2021

  Abstract

  The diagnosis of angioimmunoblastic T-cell lymphoma (AITL) is complex and requires the demonstration of a T-follicular helper (TFH) phenotype. Immunophenotypic markers that detect the TFH phenotype are highly variable, thereby necessitating the use of 3 to 5 TFH markers to substantiate a TFH phenotype. We tested the utility of germinal center markers human germinal center-associated lymphoma (HGAL) and LIM-domain only 2 (LMO2) in detecting a TFH phenotype. We compared their staining to that of 6 TFH markers in current use, PD-1, ICOS, CXCL13, SAP, CD10, and BCL6, in a cohort of 23 AITL. Our results show that although both markers can detect a TFH phenotype, HGAL was superior to LMO2 in the percent of cells stained and the intensity of staining, 2 variables used to generate H-scores. Using H-scores as the metric, HGAL was most comparable to BCL6 among the currently used TFH markers and was more sensitive than CXCL13, SAP, CD10, and LMO2. PD-1 and ICOS emerged as the most robust of the 8 markers tested in this study in detecting a TFH phenotype. We conclude that HGAL is a reliable marker of TFH cells and can aid in the diagnosis of lymphomas of TFH derivation, particularly in the recognition of early patterns of AITL.

  View details for DOI 10.1097/PAS.0000000000001852

  View details for PubMedID 34907996

• High Frequency of SARS-CoV-2 RNAemia and Association With Severe Disease. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Hogan, C. A., Stevens, B. A., Sahoo, M. K., Huang, C., Garamani, N., Gombar, S., Yamamoto, F., Murugesan, K., Kurzer, J., Zehnder, J., Pinsky, B. A. 2020

  Abstract

  BACKGROUND: Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in blood, also known as RNAemia, has been reported, but its prognostic implications are poorly understood. This study aimed to determine the frequency of SARS-CoV-2 RNA in plasma and its association with coronavirus disease 2019 (COVID-19) clinical severity.METHODS: An analytical cross-sectional study was performed in a single-center tertiary care institution and included consecutive inpatients and outpatients with confirmed COVID-19. The prevalence of SARS CoV-2 RNAemia and the strength of its association with clinical severity variables were examined and included intensive care unit (ICU) admission, invasive mechanical ventilation, and 30-day all-cause mortality.RESULTS: Paired nasopharyngeal and plasma samples were included from 85 patients. The median age was 55 years, and individuals with RNAemia were older than those with undetectable SARS-CoV-2 RNA in plasma (63 vs 50 years; P = .04). Comorbidities were frequent including obesity (37.6%), hypertension (30.6%), and diabetes mellitus (22.4%). RNAemia was detected in 28/85 (32.9%) of patients, including 22/28 (78.6%) who required hospitalization. In models adjusted for age, RNAemia was detected more frequently in individuals who developed severe disease including ICU admission (32.1 vs 14.0%; P = .04) and invasive mechanical ventilation (21.4% vs 3.5%; P = .02). All 4 deaths occurred in individuals with detectable RNAemia. An additional 121 plasma samples from 28 individuals with RNAemia were assessed longitudinally, and RNA was detected for a maximum duration of 10 days.CONCLUSIONS: This study demonstrated a high proportion of SARS-CoV-2 RNAemia, and an association between RNAemia and clinical severity suggesting the potential utility of plasma viral testing as a prognostic indicator for COVID-19.

  View details for DOI 10.1093/cid/ciaa1054

  View details for PubMedID 32965474

• Clinical and Genomic Characterization of Myeloproliferative Neoplasms Harboring PHF6 Mutations Kurzer, J., Nardi, V., Ouseph, M., Weinberg, O. NATURE PUBLISHING GROUP. 2020: 1328–29

  View details for Web of Science ID 000518328803096

• Clinical and Genomic Characterization of Myeloproliferative Neoplasms Harboring PHF6 Mutations Kurzer, J., Nardi, V., Ouseph, M., Weinberg, O. NATURE PUBLISHING GROUP. 2020: 1328–29

  View details for Web of Science ID 000518328903096

• Comparison of a Point-of-Care Assay and a High-Complexity Assay for Detection of SARS-CoV-2 RNA. The journal of applied laboratory medicine Stevens, B. n., Hogan, C. A., Sahoo, M. K., Huang, C. n., Garamani, N. n., Zehnder, J. n., Kurzer, J. n., Pinsky, B. A. 2020

  Abstract

  Numerous nucleic acid amplification assays utilizing different target genes of the SARS-CoV-2 genome have received emergency use authorization (EUA) by the United States Food and Drug Administration (FDA). Limited data are available comparing the test performance characteristics of these assays.A diagnostic comparison study was performed to evaluate the performance of the Cepheid Xpert Xpress SARS-CoV-2 assay compared to the Hologic Panther Fusion SARS-CoV-2 assay using clinical nasopharyngeal specimens. Agreement between the two assays was assessed by overall, positive, and negative percent agreement and Cohen's kappa coefficient.A total of 104 (54 positive and 50 negative) clinical nasopharyngeal samples were tested by both assays. Using the Panther Fusion as a reference standard, the Xpert demonstrated an overall agreement of 99.0% (95% confidence interval (CI): 94.8 - 100), positive percent agreement of 98.1% (95% CI: 90.1 - 100), and a negative percent agreement of 100% (95% CI: 94.2 - 100). The kappa coefficient was 0.98 (95% CI: 0.94 - 1.0). One sample positive by the Panther Fusion with a cycle threshold (Ct) of 38.6 was found to be reproducibly negative by the Xpert assay.The Cepheid Xpert Xpress SARS-CoV-2 assay provides test performance comparable to the Hologic Panther Fusion SARS-CoV-2 assay while offering laboratories rapid, on-demand testing capacity.

  View details for DOI 10.1093/jalm/jfaa135

  View details for PubMedID 32761092

• Acute Leukemias of Ambiguous Lineage: Clarification on Lineage Specificity. Surgical pathology clinics Kurzer, J. H., Weinberg, O. K. 2019; 12 (3): 687–97

  Abstract

  Acute leukemias of ambiguous lineage (ALAL) include acute undifferentiated leukemia and mixed-phenotype acute leukemia (MPAL). This article provides an overview of the diagnosis of ALAL and focuses on the data accounting for the current lineage-assignment criteria for blasts harboring more than one lineage-associated marker. In addition, the currently known molecular data are reviewed, which show that MPAL-associated gene mutations, methylation signatures, and expression profiles are a mixture of those seen in both acute myeloid leukemia and acute lymphoblastic leukemia. Finally, the prognosis and current treatments of MPAL are briefly discussed.

  View details for DOI 10.1016/j.path.2019.03.008

  View details for PubMedID 31352981

• Clinical, immunophenotypic, and genomic findings of acute undifferentiated leukemia and comparison to acute myeloid leukemia with minimal differentiation: a study from the bone marrow pathology group MODERN PATHOLOGY Weinberg, O. K., Hasserjian, R. P., Baraban, E., Ok, C., Geyer, J. T., Philip, J. S., Kurzer, J. H., Rogers, H. J., Nardi, V., Stone, R. M., Garcia, J. S., Hsi, E. D., Bagg, A., Wang, S. A., Orazi, A., Arber, D. A. 2019; 32 (9): 1373–85

  View details for DOI 10.1038/s41379-019-0263-3

  View details for Web of Science ID 000484437000014

• Impact of Pretransplant Donor BK Viruria in Kidney Transplant Recipients JOURNAL OF INFECTIOUS DISEASES Tan, S. K., Huang, C., Sahoo, M. K., Weber, J., Kurzer, J., Stedman, M. R., Concepcion, W., Gallo, A. E., Alonso, D., Srinivas, T., Storch, G. A., Subramanian, A. K., Tan, J. C., Pinsky, B. A. 2019; 220 (3): 370–76

  View details for DOI 10.1093/infdis/jiz114

  View details for Web of Science ID 000477595700005

• Impact of Pre-Transplant Donor BK Viruria in Kidney Transplant Recipients. The Journal of infectious diseases Tan, S. K., Huang, C., Sahoo, M. K., Weber, J., Kurzer, J., Stedman, M. R., Concepcion, W., Gallo, A. E., Alonso, D., Srinivas, T., Storch, G. A., Subramanian, A. K., Tan, J. C., Pinsky, B. A. 2019

  Abstract

  BACKGROUND: BK virus (BKV) is a significant cause of nephropathy in kidney transplantation. The goal of this study was to characterize the course and source of BKV in kidney transplant recipients.METHODS: We prospectively collected pre-transplant plasma and urine samples from living and deceased kidney donors and performed BKV PCR and IgG testing on pre-transplant and serially collected post-transplant samples in kidney transplant recipients.RESULTS: Among deceased donors, 8.1%(17/208) had detectable BKV DNA in urine prior to organ procurement. BK viruria was observed in 15.4%(6/39) of living donors and 8.5%(4/47) of deceased donors of recipients at our institution (p=0.50). BKV VP1 sequencing revealed identical virus between donor-recipient pairs to suggest donor transmission of virus. Recipients of BK viruric donors were more likely to develop BK viruria (66.6%vs.7.8%, p<0.001) and viremia (66.6%vs.8.9%, p<0.001) with a shorter time to onset (log-rank, p<0.001). Though donor BKV IgG titers were higher in recipients who developed BK viremia, pre-transplant donor, recipient, and combined donor/recipient serology status was not associated with BK viremia (p=0.31,0.75,0.51,respectively).DISCUSSION: Donor BK viruria is associated with early BK viruria and viremia in kidney transplant recipients. BKV PCR testing of donor urine may be useful in identifying recipients at-risk for BKV complications.

  View details for PubMedID 30869132

• Rationale and Feasibility of Using a Standardized Screening Tube on the FACSCanto II and the FACSLyric Jackson, R., Oak, J., Kurzer, J. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478081102317

• Rationale and Feasibility of Using a Standardized Screening Tube on the FACSCanto II and the FACSLyric Jackson, R., Oak, J., Kurzer, J. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478915501076

• Clinical, immunophenotypic, and genomic findings of acute undifferentiated leukemia and comparison to acute myeloid leukemia with minimal differentiation: a study from the bone marrow pathology group. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Weinberg, O. K., Hasserjian, R. P., Baraban, E. n., Ok, C. Y., Geyer, J. T., Philip, J. K., Kurzer, J. H., Rogers, H. J., Nardi, V. n., Stone, R. M., Garcia, J. S., Hsi, E. D., Bagg, A. n., Wang, S. A., Orazi, A. n., Arber, D. A. 2019

  Abstract

  Acute undifferentiated leukemia is a rare type of acute leukemia that shows no evidence of differentiation along any lineage. Clinical, immunophenotypic and genetic data is limited and it is uncertain if acute undifferentiated leukemia is biologically distinct from acute myeloid leukemia with minimal differentiation, which also shows limited myeloid marker expression and has been reported to have a poor prognosis. We identified 92 cases initially diagnosed as acute undifferentiated leukemia or acute myeloid leukemia with minimal differentiation from pathology databases of nine academic institutions with available diagnostic flow cytometric data, cytogenetic findings, mutational and clinical data. Outcome analysis was performed using Kaplan Meier test for the 53 patients who received induction chemotherapy. Based on cytogenetic abnormalities (N = 30) or history of myelodysplastic syndrome (N = 2), 32 cases were re-classified as acute myeloid leukemia with myelodysplasia related changes. The remaining 24 acute undifferentiated leukemia patients presented with similar age, blood counts, bone marrow cellularity, and blast percentage as the remaining 30 acute myeloid leukemia with minimal differentiation patients. Compared to acute myeloid leukemia with minimal differentiation, acute undifferentiated leukemia cases were characterized by more frequent mutations in PHF6 (5/15 vs 0/19, p = 0.016) and more frequent expression of TdT on blasts (p = 0.003) while acute myeloid leukemia with minimal differentiation cases had more frequent CD123 expression (p = 0.042). Outcome data showed no difference in overall survival, relapse free survival, or rates of complete remission between acute undifferentiated leukemia and acute myeloid leukemia with minimal differentiation groups (p > 0.05). Acute myeloid leukemia with myelodysplasia-related changes patients showed shorter survival when censoring for bone marrow transplant as compared to acute undifferentiated leukemia (p = 0.03) and acute myeloid leukemia with minimal differentiation (p = 0.002). In this largest series to date, the acute undifferentiated leukemia group shows distinct characteristics from acute myeloid leukemia with minimal differentiation, including more frequent PHF6 mutations and expression of TdT.

  View details for PubMedID 31000771

• Clinical, Immunophenotypic and Genomic Findings of Acute Undifferentiated Leukemia and Comparison to AML with Minimal Differentiation: A Study from the Bone Marrow Pathology Group Weinberg, O. K., Hasserjian, R. P., Baraban, E., Ok, C., Geyer, J. T., Philip, J. S., Kurzer, J. H., Rogers, H. J., Nardi, V., Stone, R. M., Garcia, J. S., Hsi, E. D., Bagg, A., Wang, S. A., Orazi, A., Arber, D. A. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-115198

  View details for Web of Science ID 000454837604162

• Flow Immunophenotyping of Benign Lymph Nodes Sampled by FNA: Representative With Diagnostic Pitfalls. Cancer cytopathology Scott, G. D., Lau, H. D., Kurzer, J. H., Kong, C. S., Gratzinger, D. A. 2018

  Abstract

  BACKGROUND: Fine-needle aspiration with flow cytometry (FNA-FC) is routinely used in the evaluation of lymph nodes suspicious for lymphoma, yet data comparing immunophenotype distributions and outliers in benign lymph nodes sampled by fine-needle aspiration (FNA) versus excision are lacking.METHODS: Flow cytometry data from 289 benign lymph node FNA cases were assessed for the overall antigen distribution, with a focus on outliers relevant to the diagnosis of lymphoma. Distributions and outlier proportions were compared with those of a separate cohort of 298 excisional biopsies.RESULTS: Compared with excisional biopsies, FNA specimens overrepresented CD3+ events (72% vs 63%), underrepresented CD19+ events (22% vs 29%), and had 25% fewer large cell-gated events. Normalized antigen distributions in FNA were equivalent to those in excisional biopsy. Twenty-three percent of FNA-FC cases exhibited an outlier, including a skewed kappa:lambda light-chain ratio, increased CD5+ or CD10+ B-cell events, a skewed CD4:CD8 ratio, and increased CD7 loss on T cells, with no significant differences in frequency or type in comparison with excisional specimens. Outliers for the light-chain ratio and T-cell antigens were enriched among older patients and included patients with a variety of autoimmune/rheumatologic conditions.CONCLUSIONS: Benign lymph node FNA yields flow immunophenotypes remarkably similar to those from excisional biopsies. Outlier flow immunophenotypes are identified in benign lymph nodes sampled by FNA at a frequency similar to that with excisional biopsies. Older patients, who have a higher baseline risk of lymphoma, are more likely to exhibit lymphoma-mimicking outliers such as a light-chain predominance on B cells and skewed CD4:CD8 ratios or increased CD7 loss on T cells, and they warrant additional diagnostic caution.

  View details for PubMedID 30194715

• Identification of early B cell precursors (stage 1 and 2 hematogones) in the peripheral blood. Journal of clinical pathology Kurzer, J. H., Weinberg, O. K. 2018

  Abstract

  Differentiating malignant B-lymphoblasts from early benign B cell precursors (hematogones) is a vital component of the diagnosis of B-lymphoblastic leukaemia. It has been previously reported that only late-stage B cell precursors circulate in the peripheral blood. Consequently, flow cytometric detection of cells with immunophenotypic findings similar to earlier stage precursors in the peripheral blood justifiably raises concern for involvement by B-lymphoblastic leukaemia. We report here, however, that benign early B cell precursors can indeed be detected in the peripheral blood, thus complicating the interpretation of flow cytometric findings derived from these sample types. A retrospective search of our collective databases identified 13 cases containing circulating early stage B cell precursors. The patients ranged in age from 15 days to 85years old. All positive cases demonstrated that the earlier B cell precursors were associated with later stage precursors, a finding that could help differentiate these cells from B-lymphoblastic leukaemia.

  View details for PubMedID 29802226

• SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression. Cell reports Lin, C., Wong, S. H., Kurzer, J. H., Schneidawind, C., Wei, M. C., Duque-Afonso, J., Jeong, J., Feng, X., Cleary, M. L. 2018; 23 (4): 1166–77

  Abstract

  Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality, necessitating further improvements in diagnosis and therapy. Targeted therapies directed against chromatin regulators are emerging as promising approaches in preclinical studies and early clinical trials. Here, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is overexpressed in pre-BCR+ ALL and required for their maintenance invitro and invivo. SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1 in a subset of ALL and suppresses expression of the cell-cycle inhibitor CDKN2C through histone H3K9 tri-methylation, thus establishing an oncogenic pathway subordinate to E2A-PBX1 that silences a major tumor suppressor in ALL. In contrast, SETDB2 was relatively dispensable for normal hematopoietic stem and progenitor cell proliferation. SETDB2 knockdown enhances sensitivity to kinase and chromatin inhibitors, providing a mechanistic rationale for targeting SETDB2 therapeutically in ALL.

  View details for PubMedID 29694893

• Identification of Early Hematogones in the Peripheral Blood Kurzer, J. H., Weinberg, O. K. NATURE PUBLISHING GROUP. 2018: 530

  View details for Web of Science ID 000429308603356

• A replicable CD271+ mesenchymal stromal cell density score: bringing the dysfunctional myelodysplastic syndrome niche to the diagnostic laboratory. Leukemia & lymphoma Gars, E., Yousry, S. M., Babu, D., Kurzer, J. H., George, T. I., Gratzinger, D. 2016: 1-3

  View details for PubMedID 27808583

• E2A-PBX1 remodels oncogenic signaling networks in B-cell precursor acute lymphoid leukemia. Cancer research Duque-Afonso, J., Lin, C., Han, K., Wei, M. C., Feng, J., Kurzer, J., Schneidawind, C., Wong, S. H., Bassik, M. C., Cleary, M. L. 2016

  Abstract

  There is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5%-7% of pediatric and 50% of pre-B-cell receptor (preBCR(+)) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL, which results in hyperactivation of the key oncogenic effector enzyme PLCγ2. Depletion of PLCγ2 reduced proliferation of mouse and human ALLs, including E2A-PBX1 leukemias, and increased disease-free survival after secondary transplantation. Mechanistically, E2A-PBX1 bound promoter regulatory regions and activated the transcription of its key target genes ZAP70, SYK, and LCK, which encode kinases upstream of PLCγ2. Depletion of the respective upstream kinases decreased cell proliferation and phosphorylated levels of PLCγ2 (pPLCγ2). Pairwise silencing of ZAP70, SYK, or LCK showed additive effects on cell growth inhibition, providing a rationale for combination therapy with inhibitors of these kinases. Accordingly, inhibitors such as the SRC family kinase (SFK) inhibitor dasatinib reduced pPLCγ2 and inhibited proliferation of human and mouse preBCR(+)/E2A-PBX1(+) leukemias in vitro and in vivo Furthermore, combining small-molecule inhibition of SYK, LCK, and SFK showed synergistic interactions and preclinical efficacy in the same setting. Our results show how the oncogenic fusion protein E2A-PBX1 perturbs signaling pathways upstream of PLCγ2 and renders leukemias amenable to targeted therapeutic inhibition. Cancer Res; 76(23); 6937-49. ©2016 AACR.

  View details for PubMedID 27758892

• Mesenchymal stromal cell density is increased in higher grade myelodysplastic syndromes and independently predicts survival. American journal of clinical pathology Johnson, R. C., Kurzer, J. H., Greenberg, P. L., Gratzinger, D. 2014; 142 (6): 795-802

  Abstract

  We retrospectively tested the prognostic and diagnostic significance of CD271+ mesenchymal stromal cell (MSC) density in cytopenic patients who underwent bone marrow biopsy to evaluate for myelodysplastic syndromes (MDS).CD271+ MSC density was quantitated by automated image analysis of tissue microarray cores in 125 cytopenic patients: 40 lower grade MDS (<5% marrow blasts), 24 higher grade MDS, and 61 benign.CD271+ MSC density was increased in higher grade MDS compared with benign (P = .006) and lower grade MDS (P = .02). CD271+ MSC density was predictive of survival among patients with MDS independent of Revised International Prognostic Scoring System (IPSS-R), history of transfusion, therapy-related MDS, and fibrosis (hazard ratio, 3.4; P < .001). Among low or intermediate IPSS-R patients, median survival was significantly shorter in the high CD271+ MSC density group (47 vs 18 months, P < .02).High CD271+ MSC density is characteristic of higher grade MDS and is associated with poor risk independent of known prognostic factors.

  View details for DOI 10.1309/AJCP71OPHKOTLSUG

  View details for PubMedID 25389333

• SH2B1 (SH2-B) and JAK2: a multifunctional adaptor protein and kinase made for each other TRENDS IN ENDOCRINOLOGY AND METABOLISM Maures, T. J., Kurzer, J. H., Carter-Su, C. 2007; 18 (1): 38-45

  Abstract

  Src homology 2 (SH2) B adaptor protein 1 (SH2B1; originally named SH2-B) is a member of a family of adaptor proteins that influences a variety of signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases. Although SH2B1 performs classical adaptor functions, such as recruitment of specific proteins to activated receptors, it also demonstrates a unique ability to enhance the kinase activity of the cytokine receptor-associated tyrosine kinase JAK2, as well as that of several receptor tyrosine kinases. SH2B1 is also among a small number of adaptor proteins shown to undergo nucleocytoplasmic shuttling, although its exact role within the nucleus is not yet clear. Deletion of the SH2B1 gene results in severe obesity and both leptin and insulin resistance, as well as infertility, which might be a consequence of resistance to insulin-like growth factor I. Thus, knockout mice support a role for SH2B1 as a positive regulator of JAK2 signaling pathways initiated by leptin, as well as of pathways initiated by insulin and, potentially, by insulin-like growth factor I.

  View details for DOI 10.1016/j.tem.2006.11.007

  View details for Web of Science ID 000243706900006

  View details for PubMedID 17140804

• Binding of SH2-B family members within a potential negative regulatory region maintains JAK2 in an active state MOLECULAR AND CELLULAR BIOLOGY Kurzer, J. H., Saharinen, P., Silvennoinen, O., Carter-Su, C. 2006; 26 (17): 6381-6394

  Abstract

  The tyrosine kinase Janus kinase 2 (JAK2) transduces signaling for the majority of known cytokine receptor family members and is constitutively activated in some cancers. Here we examine the mechanisms by which the adapter proteins SH2-Bbeta and APS regulate the activity of JAK2. We show that like SH2-Bbeta, APS binds JAK2 at multiple sites and that binding to phosphotyrosine 813 is essential for APS to increase active JAK2 and to be phosphorylated by JAK2. Binding of APS to a phosphotyrosine 813-independent site inhibits JAK2. Both APS and SH2-Bbeta increase JAK2 activity independent of their N-terminal dimerization domains. SH2-Bbeta-induced increases in JAK2 dimerization require only the SH2 domain and only one SH2-Bbeta to be bound to a JAK2 dimer. JAK2 mutations and truncations revealed that amino acids 809 to 811 in JAK2 are a critical component of a larger regulatory region within JAK2, most likely including amino acids within the JAK homology 1 (JH1) and JH2 domains and possibly the FERM domain. Together, our data suggest that SH2-Bbeta and APS do not activate JAK2 as a consequence of their own dimerization, recruitment of an activator of JAK2, or direct competition with a JAK2 inhibitor for binding to JAK2. Rather, they most likely induce or stabilize an active conformation of JAK2.

  View details for DOI 10.1128/MCB.00570-06

  View details for Web of Science ID 000239848800006

  View details for PubMedID 16914724

• Capillary electrophoresis and fluorescence anisotropy for quantitative analysis of peptide-protein interactions using JAK2 and SH2-B beta as a model system ANALYTICAL CHEMISTRY Yang, P. L., Whelan, R. J., Jameson, E. E., Kurzer, J. H., Argetsinger, L. S., Carter-Su, C., Kabir, A., Malik, A., Kennedy, R. T. 2005; 77 (8): 2482-2489

  Abstract

  Fluorescence anisotropy capillary electrophoresis (FACE) and affinity probe capillary electrophoresis (APCE) with laser-induced fluorescence detection were evaluated for analysis of peptide-protein interactions with rapid binding kinetics. The Src homology 2 domain of protein SH2-Bbeta (SH2-Bbeta (525-670)) and a tyrosine-phosphorylated peptide corresponding to the binding sequence of JAK2 were used as a model system. For peptide labeled with fluorescein, the K(d) = 82 +/- 7 nM as measured by fluorescence anisotropy (FA). APCE assays had a limit of detection (LOD) of 100 nM or 12 amol injected for SH2-Bbeta (525-670). The separation time of 4 s, achieved using an electric field of 2860 V/cm on 7-cm-long capillaries, was on the same time scale as complex dissociation allowing K(d) (101 +/- 12 nM in good agreement with FA measurements) and dissociation rate (k(off) = 0.95 +/- 0.02 s(-)(1) corresponding to a half-life of 0.73 s) to be determined. This measurement represents a 30-fold higher rate of complex dissociation than what had previously been measurable by nonequilibrium CE analysis of equilibrium mixtures. Using FACE, the protein was detected with an LOD of 300 nM or 7.5 fmol injected. FACE was not used for determining K(d) or k(off); however, this method provided better separation resolution for multiple forms of the protein than APCE. Both methods were found suitable for analysis of cell lysate. These results demonstrate that FACE and APCE may be useful complements to existing techniques for exploring binding interactions with rapid kinetics.

  View details for DOI 10.1021/ac048307u

  View details for Web of Science ID 000228605100027

  View details for PubMedID 15828784

• Tyrosine 813 is a site of JAK2 autophosphorylation critical for activation of JAK2 by SH2-B beta MOLECULAR AND CELLULAR BIOLOGY Kurzer, J. H., Argetsinger, L. S., Zhou, Y. J., Kouadio, J. L., O'Shea, J. J., Carter-Su, C. 2004; 24 (10): 4557-4570

  Abstract

  The tyrosine kinase Janus kinase 2 (JAK2) binds to the majority of the known members of the cytokine family of receptors. Ligand-receptor binding leads to activation of the associated JAK2 molecules, resulting in rapid autophosphorylation of multiple tyrosines within JAK2. Phosphotyrosines can then serve as docking sites for downstream JAK2 signaling molecules. Despite the importance of these phosphotyrosines in JAK2 function, only a few sites and binding partners have been identified. Using two-dimensional phosphopeptide mapping and a phosphospecific antibody, we identified tyrosine 813 as a site of JAK2 autophosphorylation of overexpressed JAK2 and endogenous JAK2 activated by growth hormone. Tyrosine 813 is contained within a YXXL sequence motif associated with several other identified JAK2 phosphorylation sites. We show that phosphorylation of tyrosine 813 is required for the SH2 domain-containing adapter protein SH2-B beta to bind JAK2 and to enhance the activity of JAK2 and STAT5B. The homologous tyrosine in JAK3, tyrosine 785, is autophosphorylated in response to interleukin-2 stimulation and is required for SH2-B beta to bind JAK3. Taken together these data strongly suggest that tyrosine 813 is a site of autophosphorylation in JAK2 and is the SH2-B beta-binding site within JAK2 that is required for SH2-B beta to enhance activation of JAK2.

  View details for DOI 10.1128/MCB.24.10.4557-4570.2004

  View details for Web of Science ID 000221440900042

  View details for PubMedID 15121872