bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Colony-Stimulating Factor 3 Receptor M696T Mutated in a Patient with Ph+ Acute Lymphoblastic Leukemia
Authors: Chen Xin , Wang Bichen , Pang Aiming , Jiang Erlie , Chu Yajing , Yuan Weiping , Feng Sizhou , Han Ming-Zhe 
Published: February 2021

Purpose: Colony-stimulating factor 3 receptor (CSF3R) mutations have been identified in a variety of myeloid disorders, such as severe congenital neutropenia (SCN), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and atypical chronic myelogenous leukemia (aCML). Although CSF3R point mutations (e.g., T618I) are emerging as key players in CNL/aCML, the significance of rarer CSF3R mutations is unknown. We report a case of philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) with the M696T mutation in CSF3R gene and assess the pathogenicity of the CSF3R M696T mutation in Ph+ ALL.
Experimental Design: Here we report on a 32-year-old female who presented with asthenia. The initial hematological workup revealed white blood cell (WBC) count of 97 x 109/L (normal range 4-10 x 109/L). There was 84% prolymphocyte in the bone marrow. The immunophenotype of the blasts as judged from flow cytometry was in accordance with a B-ALL. The fusion gene for BCR-ABL P210 was positive. Hot mutation closely related to diseases was: CSF3R (nucleotide change c.2087 T&gt;C, amino acid change p.M696T, mutation frequency 50.4%). Cytogenetic analysis showed 46, XX, t (9;22) (q34;q11). The patient was diagnosed as Ph+ ALL with the CSF3R M696T mutation and achieved Long-term survival after unrelated donor hematopoietic stem cell transplantation. Meanwhile we performed a series of experiments using murine interleukin 3 (IL-3)-dependent Ba/F3 cell line to evaluate the transforming capacity of the CSF3R M696T mutation. The phosphorylation of STAT3 was analyzed by G-CSF dependence assays and immunoblot analysis to evaluate the CSF3R M696T mutation contribution to the tumor transformation ability of Ba/F3 cells.
Results: This patient achieved complete remission with chemotherapy in combination with tyrosine kinase inhibitor (TKI) and long-term survival by unrelated donor transplantation. We confirmed the presence of a CSF3R M696T germline mutation in this patient, and the mutation was inherited from her mother. The experiments in vitro result showed the CSF3R M696T mutation harbors marginal contribution to the tumor transformation ability of Ba/F3 cells. CSF3R M696T mutation was neutral in tumor transformation ability.
Conclusions: We believe that TKI is still effective in patients with the CSF3R M696T mutation in Ph+ ALL. Donor with CSF3R M696T mutation might still be selected.

Disclosures
No relevant conflicts of interest to declare.
Frequency of IKZF1 Deletions in a Peruvian Population with B-Cell Acute Lymphoblastic Leukemia
Authors: Enriquez Daniel J , Mitchell Rachel J. , Alapi Krisztina Zuborne , Cervantes Elizabeth , Cancino Karina , Casas Jhoysi , Valcarcel Bryan , Sandival Gustavo , Haro Juan C , Samanez-Figari Cesar , Zapata Arturo , Garcia-Leon Juan L , Fielding Adele K. 
Published: February 2021

Frequency of IKZF1 Deletions in a Peruvian Population with B-cell Acute Lymphoblastic Leukemia
Background: B-cell Acute Lymphoblastic Leukemia (B-ALL) is an aggressive disease with worse outcomes in older patients, and latino ethnicity. Additionally, Latino populations are at higher risk of developing B-ALL.IKZF1is an essential lymphoid transcription factor with deletions (ΔIKZF1)implicated in treatment failure and relapses. We aimed to evaluate the frequency ofIKZF1deletions in a cohort of Peruvian patients with newly diagnosed B-ALL.
Methods: We collected diagnostic bone marrow samples from 41 consecutive patients with B-ALL diagnosed between 2015-2019 at Instituto Nacional de Enfermedades Neoplasicas (INEN; Lima, Peru). Bone marrow samples were cryopreserved prior to induction treatment. DNA was extracted using High Pure PCR Template Preparation Kit (Roche) at INEN. Samples with adequate DNA were screened forΔIKZF1by multiplex endpoint PCR covering four main deletions - dominant negative Δ4-7 or the loss of function Δ2-7, Δ4-8, and Δ2-8 IKZF1 deletions at UCL Cancer Insitute (London, UK) using the primers described by Caye et. al. We analyzed outcomes byIKZF1status.
Results: Forty-one cases were enrolled during the study period. Clinical characteristics are presented in Table 1. Median age was 20 years[1-63]. Fifteen∆IKZF1cases (37%) were detected (67%BCR-ABL1 negand 33%BCR-ABL1pos).Cases withΔIKZF1were older than those with wild-typeIKZF1(median age 31 vs 13 years, p=0.002). Median presenting white blood count (WBC) was 48 x109/L [R:2-218], with a higher WBC inΔIKZF1compared to wild-type (87 vs 24 x109/L, p=0.001). The most frequent deletion was ∆4-7 (sevenBCR-ABL1 negand threeBCR-ABL1 pos) additional deletions are described in table 2. All patients received intensive 'pediatric-based' treatment, 21 with BFM-2009 and 19 with the CALGB 10403 protocol. CR rates after induction were 67% and 92% for∆IKZF1and wild-type cases, respectively. Eleven (73%) of patients with∆IKZF1subjects (73%) were MRD positive by flow cytometry after induction compared to 11 (44%) among wild-type. At a median follow-up of 2 years EFS was 38% in the∆IKZF1group and 58% in the wild type group, correspond OS was 38% and 58%, respectively.
Conclusion: A high frequency of IKZF1 deletions was found in a Peruvian population with B-ALL and was associated with older age and higher presenting white blood counts. Prospective studies with larger Latino population are warranted to confirm this finding.

Disclosures
No relevant conflicts of interest to declare.
Association of Blood Type on Clinical Outcomes in Black/African Americans Hospitalized for COVID-19 Infection
Authors: Cheng Yan , Mohammed Sharif , Okoh Alexis , Lee Ki (Steve) , Raczek Corinne , Krushna Amin , Cohen Alice J. , Nagarakanti Sandhya 
Published: February 2021

Introduction: Early studies from Wuhan, China have reported an association between blood type and outcomes in COVID-19 infected patients. Conflicting reports in literature have investigated the protective role of blood type O against worst outcomes associated with COVID-19 infections. Approximately 50% of Black/African Americans (AA) have blood group O. Our study is the only study to date looking at the association between Black/AA and blood type. We aimed to determine the association between blood type and Black/AA patients hospitalized for COVID-19.
Methods: We retrospectively reviewed data on patients with known blood type, who were admitted for COVID-19 at a single center between March and April 2020. We excluded other races in our study because only about 2% of the population was Caucasian and 8% representing other races, representing a small subset of patients under study whereas Black/AA represented about 90% of our hospitalized patients. Patients were stratified into 4 groups based on their ABO blood type. Baseline demographic, clinical characteristics and clinical course of the disease were compared. The primary end point was in-hospital mortality. Secondary endpoints included admission to the intensive care unit (ICU), acute kidney injury requiring hemodialysis and length of stay (LOS).
Results: During the study period, a total of 256 patients were reviewed. Distribution of ABO type was as follows; A: (N=65) 25%, B: (N=62) 24%, AB: (N=9) 4%, O: (N=120) 47%. Compared to blood types A, B and O, AB patients were younger (mean; yrs. 63 vs. 63 vs. 62 vs. 43 yrs. p=0.0242). Blood type B patients were more likely to present with nausea, than groups A, AB, and O. (27% vs. 10% vs. 0% vs. 5%; p=0.017). All other characteristics including baseline inflammatory markers were comparable. There was no difference among groups regarding in-hospital mortality (A: 39% B: 29% AB: 33% O: 31% p value: 0.676) or admission to the ICU (A:31% B: 28% AB: 33% O: 34% p value: 0.840). The incidence of acute kidney injury requiring hemodialysis was higher in blood type A patients compared to B, AB, and O. (31% vs. 0% vs. 23% vs. 19%; p=0.046). In hospital LOS was comparable among all groups.
Conclusions: In this single center analysis of black/AA patients admitted for COVID-19, there was no association between blood type and in-hospital mortality or admission to ICU. Blood type A patients had a higher propensity of kidney injury, but this did not translate into worse in-hospital survival.

Disclosures
Cohen: GBT: Speakers Bureau.
Minimal Residual Disease Assessment Is an Independent Prognostic Factor in Splenic Marginal Zone Lymphoma
Authors: Lv Ryu , Wang Yi , Wang Tingyu , Wenjie Xiong , Wang Huijun , Yan Yuting , Wang Qi , Liu Wei , An Gang , Huang Wenyang , Sui Weiwei , Xu Yan , Yu Zhen , Zou Dehui , Wang Jianxiang , Qiu Lugui , Yi Shuhua 
Published: February 2021

Purpose: Splenic marginal lymphoma (SMZL) is a rare indolent B-cell lymphoma with long survival. The minimal residual disease (MRD) detection in indolent B-cell lymphomas has shown power in predicting survival and even in guiding treatment duration in chronic lymphocytic leukemia. As almost all SMZL patients have bone marrow involvement (BMI) at diagnosis, we prospectively designed the MRD detection during treatment to study its prognostic value in SMZL.
Methods: SMZL patients who needed chemotherapy would regularly monitor the MRD status until undetectable MRD by multiparameter flow cytometry (MFC). Patients with MRD under 0.01% were defined as uMRD. Other clinical factors were also analysed as prognostic factors.
Results: In total, 71 patients with frontline therapy were enrolled in this study. There were 284 evaluable BM MRD samples. At end of treatment, 55 patients (77.4%) got uMRD, 10 patients had a MRD level of 0.01-1%, and 6 patients had a MRD level of ≥ 1%. The uMRD rate increased at the end of treatment. With a median follow-up of 50 (24-157) months, uMRD patients showed superior outcomes compared with MRD-positive patients. Patients with uMRD had a significant better progression free survival (PFS) compared to those with MRD. PR with positive-MRD after induction therapy was a significantly poor predictor for PFS and overall survival (OS). Multivariate prognostic analysis showed it was a powerful independent prognostic factor for PFS [HR=0.357 (95%CI 0.131-0.972), P=0.044].
Conclusion: uMRD in BM was an independent prognostic factor in SMZL patients, especially for the patients only achieving PR at the end of therapy.
Figure

Disclosures
No relevant conflicts of interest to declare.
Long-Term Follow-up of a Randomized Trial of Two Dose Levels of Antithymocyte Globulin in Haploidentical Hematopoietic Stem Cell Transplantation
Authors: Wang Yu , Lin Ren , Xu Lan-Ping , Liu Kai-Yan , Zhang Xiao-Hui , Liu Qi-Fa , Huang Xiao-Jun 
Published: February 2021

Background The optimal dose of antithymocyte globulin (ATG) with respect to the prevention of graft-versus-host disease (GVHD) following haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is under investigation. In our previous single-center randomized study, as compared with 6 mg/kg ATG, 10 mg/kg ATG was found to be associated with better GVHD prevention and superior GRFS, but an increase in infection-related deaths. Later on, in our multi-center randomized trial, 7.5 mg/kg ATG for GVHD prophylaxis was associated with reduced EBV and CMV infections without increased incidence of GVHD in comparison with 10.0 mg/kg ATG in haplo-HSCT.
Methods We reanalyzed and updated the prospective, randomized trial (clinicaltrials.gov, NCT01883180) identifying the influence of 7.5mg/kg versus 10.0 mg/kg of ATG on clinical outcomes in haplo-HSCT with extended follow-up (N=145. Seventy-six patients received 7.5 mg/kg ATG (ATG-7.5), whereas the remaining patients received 10 mg/kg ATG (ATG-10).
Results The median follow-up period was 1702 days (range, 23-2036 days). The rate of infection-related deaths in ATG-10 arm was double that of the ATG-7.5 arm (20.0% vs 11.8%; P=0.024). The 5 year cumulative incidence of relapse was not significantly different between the ATG-7.5 and ATG-10 groups (16.8% vs. 5.7%, P = 0.053). The 5 year cumulative incidence of non-relapse mortality was comparable between the ATG-7.5 and ATG-10 groups (27.6% vs. 28.7%, P = 0.938). The 5 year cumulative incidence of chronic GVHD (46.7% vs. 48.3%, P = 0.913), moderate-to-severe chronic GVHD (32.8% vs. 25.3%, P = 0.248), and severe chronic GVHD (17.1% vs. 13.3%, P = 0.505) were comparable between the ATG-7.5 and ATG-10 groups. The 5 year probabilities of disease-free survival (DFS) in the ATG-7.5 and ATG-10 groups were 55.6% and 65.7%, respectively (P = 0.281). The 5 year probability of GVHD-free/relapse-free survival (GRFS) in the ATG-10 group was significantly higher than that in the ATG-7.5 group (48.1% vs. 29.5%, P = 0.020). The 5 year cumulative incidence of late effects of grades 1-5 (67.2% vs. 71.2%, P = 0.695) and multiple late effects (26.2% vs. 25.4%, P = 0.920) were comparable between the ATG-7.5 and ATG-10 groups. In multivariate analysis, ATG-7.5 was associated with a significantly lower GRFS compared to ATG-10 (hazard ratio, 1.819; 95% confidence interval, 1.106-2.994; p=0.019).
Conclusion it appears that 10 mg/kg ATG was found to be associated with superior GRFS and comparable GVHD and late effects, but an increase in infection-related deaths as compared with 7.5 mg/kg ATG for haplo-HSCT.
Figure

Disclosures
No relevant conflicts of interest to declare.
Interleukin-2 Receptor Alpha Chain, Also Called CD25, Is a Potential Target in Acute Lymphoblastic Leukemia
Authors: Carrà Giovanna , Cartellà Antonio , Maffeo Beatrice , Circosta Paola , Cignetti Alessandro , Pautasso Marisa , Familiari Ubaldo , Volante Marco , Dragani Matteo Emidio Emidio , Rege Cambrin Giovanna , Saglio Giuseppe , Morotti Alessandro 
Published: February 2021

Background: Acute lymphoblastic leukemia (ALL) is a molecularly heterogeneous disease originating from clonal proliferation of precursor B-lineage cells. In adults, ALL diagnosis is still associated with a dismal prognosis due to the lack of specific targeted therapies. This study was designed to investigate the expression of interleukin-2 receptor alpha chain CD25 in B-ALL and its biological significance, especially following the availability of specific CD25 targeting compounds.
Methods:The expression of IL2RA (CD25 gene) was detected by flow cytometry (FC), immunohistochemistry and Western blot analysis, in 25 newly diagnosed ALL patients, both Philadelphia positive (12 patients) and Philadelphia negative (13 patients). Similarly, CD25 expression was assessed in four B-ALL commercially available cell lines. Infection with shRNA specifically directed against CD25 was used to evaluate apoptosis induction and cell cycle arrest in primary B-ALL cells established from two patients.
Results:Our data suggest that ALL, and in particular Ph-positive ALL, aberrantly expresses the interleukin-2 receptor alpha chain, CD25. Whereas normal B cells display low amounts of CD25, primary ALL cells and ALL cell lines (over)-express CD25. While the high frequency of CD25 on the surface of many different hematological tumor cells has been established and confirmed in our study, there is little investigation focusing on the significance of CD25 expression. Indeed, CD25 may be present on ALL cells and enable oncogenic signaling pathways. In such respect, we observed that CD25 silencing in primary cells promotes cell cycle arrest and apoptosis induction. While these data support the rational to target CD25, ALL cells did not appear to be in-vitro sensitive to basiliximab, an antibody able to target the Il2RA, but in-vivo investigations are needed to better assess the effects of this therapeutic approach in ALL context.
Conclusions:We concluded that CD25 expression is elevated in patients with B-ALL. Our results also demonstrate that CD25 silencing induces cell cycle arrest and apoptosis. The latter result has important implications from a therapeutic point of view. Targeting CD25 receptor with anti-CD25 antibodies or peptide mimetics could be an effective strategy for targeting leukemic cells. Additionally, high CD25 expression could be exploited for the development of CAR-T therapy

Disclosures
Saglio: Roche:Research Funding;Pfizer:Research Funding;Incyte:Research Funding;Novartis:Research Funding;Ariad:Research Funding;Bristol-Myers Squibb:Research Funding.
Overexpression of hTLX3 in Association with Mutant IL7Rα Is Sufficient to Generate T-ALL In Vivo and to Transform Thymocytes in
Vitro
Authors: Rodrigues Gisele Olinto Libanio , Hixon Julie , Winer Hila , Matich Erica , Andrews Caroline , Cramer Sarah , Li Wenqing , Durum Scott 
Published: February 2021

Mutations of the IL-7Rα chain occur in approximately 10% of pediatric T-cell acute lymphoblastic leukemia cases. While we have shown that mutant IL7Ra is sufficient to transform an immortalized thymocyte cell line, mutation of IL7Ra alone was insufficient to cause transformation of primary T cells, suggesting that additional genetic lesions may be present contributing to initiate leukemia. Studies addressing the combinations of mutant IL7Ra plus TLX3 overexpression indicates in vitro growth advantage, suggesting this gene as potential collaborative candidate. Furthermore, patients with mutated IL7R were more likely to have TLX3 or HOXA subgroup leukemia. We sought to determine whether combination of mutant hIL7Ra plus TLX3 overexpression is sufficient to generate T-cell leukemia in vivo. Double negative thymocytes were isolated from C57BL/6J mice and transduced with retroviral vectors containing mutant hIL7R plus hTLX3, or the genes alone. The combination mutant hIL7R wild type and hTLX3 was also tested. Transduced thymocytes were cultured on the OP9-DL4 bone marrow stromal cell line for 5-13 days and accessed for expression of transduced constructs and then injected into sublethally irradiated Rag-/- mice. Mice were euthanized at onset of clinical signs, and cells were immunophenotyped by flow cytometry. Thymocytes transduced with muthIL-7R-hTLX3 transformed to cytokine-independent growth and expanded over 30 days in the absence of all cytokines. Mice injected with muthIL7R-hTLX3 cells, but not the controls (wthIL7R-hTLX3or mutIL7R alone) developed leukemia approximately 3 weeks post injection, characterized by GFP expressing T-cells in blood, spleen, liver, lymph nodes and bone marrow. Furthermore, leukemic mice had increased white blood cell counts and presented with splenomegaly. Phenotypic analysis revealed a higher CD4-CD8- T cell population in the blood, bone marrow, liver and spleen compared in the mutant hIL7R + hTLX3 mice compared with mice injected with mutant IL7R alone indicating that the resulting leukemia from the combination mutant hIL7R plus hTLX3 shows early arrest in T-cell development. Taken together, these data show that oncogenic IL7R activation is sufficient for cooperation with hTLX3 in ex vivo thymocyte cell transformation, and that cells expressing the combination muthIL7R-hTLX3 is sufficient to trigger T-cell leukemia in vivo.
Figure

Disclosures
No relevant conflicts of interest to declare.
Comparative Transcriptomics of Alpha-Beta Subcutaneous Panniculitis-like T-Cell Lymphoma and Primary Cutaneous Gamma Delta T-Cell Lymphoma
Authors: Li Xing , Severson Kevin J , Patel Meera H , Brumfiel Caitlin M , Hughes Alysia , DiCaudo David , Comfere Nneka , Sluzevich Jason , Rosenthal Allison C. , Torres-Cabala Carlos A , Pittelkow Mark R , Mangold Aaron R 
Published: February 2021

Background: Subcutaneous lymphomas are a heterogeneous group of diseases with variable clinical behavior that ranges from a lymphoproliferative disorder to an aggressive cytotoxic lymphoma. Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an uncommon, often indolent cutaneous lymphoma that localizes to the subcutaneous adipose tissue. These tumors exhibit an alpha/beta phenotype (abSPTCL). Primary cutaneous gamma-delta T-cell lymphoma (PCgdTCL) is a rare, highly aggressive lymphoma that frequently involves the subcutaneous adipose tissue. The goal of this study is to identify key inflammatory and oncogenic pathways in SPTCL and PCgdTCL to determine which mutational or expression patterns differentiate abSPTCL and PCgdTCL. A comprehensive catalog of cancer gene expression profiles generated via RNA sequencing on patient samples is essential to understand tumorigenesis and to develop effective therapies.
Methods: We performed transcriptomic profiling analysis using RNA sequencing in lesional skin biopsies from patients of abSPTCL (n=10), PCgdTCL (n=9), and controls (n=5). Differential analyses were performed on the entire transcriptomic profiles among the 3 groups.
Results: Although the transcriptomic profiles of abSPTCL and PCgdTCL samples had similarities, there were notable differences between these groups that may elucidate unique pathways that propagate each disease. In contrast to abSPTCL, PCgdTCL samples demonstrated upregulation of cell motility and proliferation, and downregulation of pathways involving apoptosis and tumor necrosis factor production. The most significantly upregulated gene pathways in both abSPTCL and PCgdTCL samples were those involving immune and inflammatory response, viral defense, type I interferon signaling, interferon-gamma-mediated signaling, and positive regulation of T cell proliferation. The most significantly downregulated gene pathways in the two groups were those involving cell adhesion, rRNA processing and translation, and extracellular matrix organization. The top 5 upregulated immune response and downregulated cell adhesion hub genes for abSPTCL highlighted by gene interaction network analysis included: TNF, CTLA4, CD86, IL10, CCR5 & ITGB5, ITGA8, VWF, APP, CDH5, respectively.
Conclusion: Our transcriptomic profiling pinpoints disease-related enrichment pathways and gene functions in abSPTCL and PCgdTCL patients, which may shed light on molecular mechanisms that drive disease activity. Hub genes in abSPTCL represent potential drug targets for further development of novel therapies.

Disclosures
Mangold: Kirin:Membership on an entity's Board of Directors or advisory committees;Elorac:Research Funding;Sun Pharma:Research Funding;MiRagen:Research Funding;Solagenix:Research Funding.