bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence of Autoimmune Diseases, Molecular Characteristics and Clinical Outcomes of Chronic Myelomonocytic Leukemia in an Asian Population: A Single-Center Experience
Authors: Ponvilawan Ben , Tunsing Pattaraporn , Sukpanichnant Sanya , Owattanapanich Weerapat 
Published: November 2021

Abstract
Background: Chronic myelomonocytic leukemia (CMML) is the most common subtype of the rare myelodysplastic/myeloproliferative neoplasms. Some studies have described the possible association with autoimmune disease. With the potential transformation into acute myeloid leukemia, it is known to have an unfavorable prognosis. Previous studies reported TET2, SRSF2, ASXL1, and KRAS/NRAS as the most occurring somatic mutations in CMML. However, the clinical and molecular characteristics of CMML patients in Asia remained fairly unknown.
Materials and Methods: Patients with CMML who were diagnosed in Siriraj Hospital, which is the largest comprehensive cancer center in Thailand, from 2010 to 2020 were identified from the hospital database. Clinical and laboratory data, along with pathological results, were collected from the same database. The results of the 25-gene targeted DNA sequencing panel designed for myeloid neoplasms were also extracted if the results were available. Continuous variables were represented as medians and their associated ranges. Overall survival (OS) was determined using Kaplan-Meier estimator and log-rank test.
Results: A total of 67 patients with CMML were included in our study. The median age of the cohort was 67 years old with a similar number of male and female patients in the cohort. Thirteen (19.4%) patients were diagnosed with autoimmune diseases, mainly autoimmune hemolytic anemia and immune thrombocytopenic purpura. According to cytogenetic risk for CMML, 35 (64.8%), 6 (11.1%), and 13 (24.1%) patients were classified as low, intermediate, and high risk, respectively. The clinical characteristics and laboratory results of patients were shown in Table 1. For the 15 patients with available molecular results, 13 had at least 1 somatic abnormality with TET2 (46.7%), ASXL1, NRAS, SRSF2 (each 26.7%), and KRAS (20.0%) being the common genetic mutations. The median mutation number was 4 (range, 0-6). The molecular landscape was demonstrated in Figure 1. Overall survival (OS) rates at 1 and 2 years were 74% and 57%, respectively. Patients with MDS-CMML tended to have longer median OS compared to MPN-CMML [37.9 (13.6-62.2) months vs. 19.7 (10.1-29.4) months] but did not reach statistical significance (p=0.124) (Figure 2).
Conclusions: Asian patients with CMML had a considerable amount of associated autoimmune diseases. The genetic mutations contributing to CMML in our cohort also differed from previous reports.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Palbociclib and Ponatinib Suppress Acute Myeloid Leukemia in Patient-Derived Xenograft
Authors: Busa Daniel , Loja Tomas , Jeziskova Ivana , Folta Adam , Mayer Jiri , Culen Martin 
Published: November 2021

Abstract
Aims: Palbociclib, a breast cancer approved CDK4/6 inhibitor, and ponatinib, a BCR/ABL1 inhibitor with a multi-kinase activity approved for chronic myeloid and acute lymphoid leukemia, were previously shown to be effective in vitro against acute myeloid leukemia (AML). Here, we aimed to test this effect in a patient-derived xenograft model.
Methods: Two newly diagnosed AMLs (AML #1: myelomonocytic AML, intermediate cytogenetic risk; AML #2: AML with myelodysplasia-related changes, poor cytogenetic risk) were xenotransplanted into NOD SCID gamma mice. Treatment was initiated at detection of approximately 5-20% hCD45+ cells in mouse peripheral blood (PB). Palbociclib, ponatinib, vehicle, and venetoclax as a comparative treatment, were administered orally for 3 weeks, 5 days per week. Chemotherapy (cytarabine+doxorubicine, AraC/Dox) 5+3 regimen served as a positive control. Azacitidine served as another comparative drug and was administered subcutaneously, five days per week in 3 cycles - 1 week on, 1 week off.
Results: Significant reduction of disease burden and prolongation of overall survival (OS) were seen with palbociclib and the reference treatment venetoclax in both AMLs, and with chemotherapy in AML#1 (Fig. 1). Ponatinib prolonged OS in AML#1 but failed to provide reduction of disease burden in PB. Interestingly, azacitidine induced the longest remission (&lt;1% hCD45+ cells in PB), for almost 10 weeks, but only in 2/4 mice for AML#2. Treatment toxicity manifested by weight decrease was only seen with chemotherapy (AML#1: 24% weight loss, p = 0.0001; AML#2: 19% loss, p = 0.04), and was also accompanied with early mouse mortality in 3/4 mice for AML#2. None of the tested treatments lead to complete AML eradication and a gradual relapse was seen in PB. The AML infiltration was higher in bone marrow than in spleen at final analysis at relapse (AML#1, 83 vs 73% of hCD45+ cells, mean, p = 0.02; AML#2, 95 vs 65%, p = 0.0001). No changes in AML phenotype were observed between treated and vehicle mice in case of AML#1, except for azacitidine which decreased monocyte (SSCdim, CD45high; 94 vs 96%, mean, p = 0.03), CD34+ (2 vs 5%, p = 0.01) and primitive CD34+CD38- cell (0.1 vs 0.3%, p = 0.005) percentages. For AML#2, blast (SSClow, CD45dim) percentage compared to vehicle (70%) was decreased by chemotherapy (24%, p = 0.01) and increased by venetoclax (80%, p = 0.03) and azacitidine (87%, p = 0.03); monocytes (6% for vehicle) were decreased by chemotherapy (1%, p = 0.004), venetoclax (3%, p = 0.01), and azacitidine (0%, p = 0.008); CD34+ cells were increased by venetoclax (59 vs 39%, p = 0.02).
Summary: Palbociclib, and partially ponatinib, demonstrated AML suppression in vivo. This encourages further investigation of their efficacy in different AML subtypes and in combination with other drugs.
Funding: Supported by MUNI/A/1595/2020.
Figure 1 Figure 1.

Disclosures
Mayer: AOP Orphan Pharmaceuticals: Research Funding.
Haploidentical Peripheral Blood Stem Cell Transplantation (Haplo-PBSCT) with Cyclophosphamide Pos Transplant (CyPost) in High-Risk Hematologic Malignancies. Results of 5 Years in Transplant Center in Northeast of Mexico
Authors: Baltazar Severiano , Pequeño Luevano Myrna Patricia , González Villarreal Guadalupe , Sotomayor Duque Guillermo , Ramos Vazquez Raul , Cruz Contreras Diego , Guajardo Leal Martha Lilia , Sorkee Davila Helga Patricia , Carrizalez Villarreal Jose Alfredo , Cedillo Jose Luis , Ramirez López Alba Nydia , Borjon Cabada Isabel , Quirino Marquez Christian , Mecott Estudillo Arantxa , Avila Contreras Gerardo , Nava Gutiérrez Willy , Aldama Gutiérrez Dora , Garza Escobar Juan Daniel , Garcia Cerda Yarezi , Valerio Bugarin Victor , Machuca Adame Karen , Gudiño Cobos Luis Omar , De Leon Cantu Rosa Elva , Hernadez Valdez Roberto 
Published: November 2021

Abstract
Introduction: Haploidentical peripheral blood stem cell transplantation ( Haplo-PBSCT) is a curative option in patient with hematology malignancy. In Mexico is very difficult to find an identical HLA donor , for this reason Haplo PBSCT it is an option in our public Health institution.
Materials and methods: we aimed a retrospective study since (2017 -2021) in our Hospital Unidad Médica de alta Especialidad 25, Instituto Mexicano del Seguro Social (IMSS UMAE 25) Monterrey, Mexico. We include patients over 15 years of age who were undergo Haplo PBSCT with hematolgy malignancies . We performed Analysis of Overall and Relapse-free survival with kaplan meier curves and incidence of acute and chronic graft versus host disease (GVHD) and percentage of Transplant-Related Mortality (TRM).
Results: we analized a 38 patients, the median age was 35 years (range 15-64). Of the total , 25 were male (65%) and 13 famale (34%). The rest of baseline data is described in table 1.
The median time of neutrophil engrafment was days 17 ( 11-26 ) and platelets was 19.5 days ( 12-38 ). The Incidence of Primary Graft failure was 18 % ( seven patients). Patients with graft had 99-100% chimerism at day 100. The Incidence of aGVHD was 26 % and the cGVHD was 16%. DLI was used in four patients to treat passenger lymphocyte syndrome (2 patients) and ( 2 patients) with severe graft rejection.
The principal cause of death was sepsis in eleven patients (29%). Two patients with acute leukemia (AML and ALL) died after development of post transplant lymphoproliferative disease. The TRM was 28.2%. There were no relapse-related deaths during follow-up after Haplo-PBSCT.
The median of survival was 4.5 months ( range 1-44) with Overall Survival (OS) of 42 % at 3 years ( figure 1).
Conclusion: Our analysis shows results that were comparable with those published in first world international transplant centers . Relapse remains the major cause of transplant failure, in our population the antigenic disparity between donor and recipient can strengthen the immune response versus disease. Haplo-PBSCT is a feasible transplantation method in patients with hematological malignancies in developing countries with limited resources.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Racial Disparity in Mortality Rates Among Black and White Americans with Multiple Myeloma
Authors: Akinyemi Oluwasegun Austine , Ogunbona Oluwaseun B , Abodunrin Faith O , Oni Olanrewaju 
Published: November 2021

Abstract
Background: In the United States, Multiple myeloma (MM) is the second most common hematologic malignancy and the most common hematologic malignancy in blacks. It is a fatal plasma cell dyscrasia with a median overall survival of 5 to 10 years. Different studies have highlighted a racial disparity in survival outcomes between Blacks and Whites patients' population with MM. However, the reason for the observed racial disparity in survival outcomes is not clearly understood.
Aim: To explore the role of socioeconomic variables including access to insurance and, median Income on the racial disparity in outcome among patients with MM.
Method: We conducted a retrospective analysis of all hospitalizations associated with the primary diagnosis of MM in the National Inpatient Sample (NIS 2008-2014) database using the relevant International Classification of Diseases, Ninth Revision, Clinical Modification codes. The study outcome was the mortality rates between black patients and a propensity score matched control group of white patients with MM.
Result: There were 185,000 MM associated hospitalization in the NIS (2008-2014). Among the study population, 66.7% were whites, 20.8% were blacks, and 7.7% were Hispanics. The mean age was 66.5 years for blacks and 70.2years for whites. Among the Black population, 21.6% had private insurance compared to 25.1% of their White counterparts. Also, 45.6% of Black participants were in the lowest income quartile compared to only 19.6% of Whites. Only 13.5% of Blacks were in the highest income quartile compared to 28.7% of Whites. 73.4% of Blacks were on public insurance compared to 70.9% of Whites. There was no difference in the mortality rate between blacks and a control group of whites matched for insurance, median income, sex and age (49.4% vs 50.6%, p =0.42).
Conclusion: Multiple myeloma may not be more deadly in Blacks compared to Whites, and the observed disparity in outcomes in the literature are likely due to the effects of social determinants of health such as income and access to insurance.

Disclosures
No relevant conflicts of interest to declare.
New Approach to Decipher GATA2 Deficiency Syndrome: Focus on the Recurrent GATA2 R396Q Mutation
Authors: Largeaud Laetitia , Jamrog Laura , Fregona Vincent , Hamelle Camille , Dufrechou Stephanie , Prade Naïs , Hebrard Sylvie , Sellam Esmaa , Bayet Manon , Didier Christine , Gerby Bastien , Delabesse Eric , Pasquet Marlene , Broccardo Cyril 
Published: November 2021

Abstract
Germline GATA2 mutations are identified in a complex disorder termed GATA2 deficiency syndrome. Clinical heterogeneous manifestations are associated with a wide diversity of molecular alterations (missense, frameshift, nonsense, intronic or splicing mutations). Truncating mutations decrease GATA2 expression suggesting a haploinsufficiency mechanism while molecular consequences of missense mutations are ill-known. We focus our research on the most recurrent GATA2 mutation, GATA2 R396Q.
Our in vitro results indicate that the ectopic expression of GATA2 R396Q has a strong impact on the clonogenicity associated with an excessive granulocyte differentiation. This data motivates the elaboration of a more physiological approach through the development of a new knock-in mouse model with endogenous expression of Gata2 R396Q mutation. This model allowed us to address the question of the impact of this missense mutation on hematopoiesis at steady state and in challenging conditions.
The Gata2R396Q/+ mice showed an abnormal distribution of the immature progenitors Lin - Sca-1 + Kit + (LSK) subpopulations, mainly defines by an increase of the number of aberrant Long-Term Hematopoietic Stem cells (LT-HSC) contrasting with the decrease of LT-HSC population in Gata2+/- mouse model. Functional assays on Gata2R396Q/+ LSK cells revealed also qualitative defects. Indeed, their reconstitution capacity and their response to inflammatory or chemotherapy stimuli seemed to be largely affected. To address at the molecular level the impact of the missense mutation in these progenitors, we combined gene expression analysis with chromatin gene accessibility. These analyses revealed a strong disruption of the cells' ability to respond to stimuli, such as IFN or TNFα signaling, confirming what we observed at the cellular level in functional assays. Furthermore, specific RNA sequencing of the LT-HSC, ST-HSC and MPP3-4 subpopulations showed that the majority of these molecular perturbations are detected in every subpopulation of the LSK cells. In addition, we are able to establish a precise genetic signature in LT-HSC that may be related to their major functional defects.
Combination of in vitro and in vivo approaches leads to improve our understanding of GATA2 deficiency syndrome. Modelization of the most recurrent germline Gata2 mutation revealed a different phenotype than the haploinsufficient mouse model. Furthermore, expression of Gata2 R396Q mutation qualitatively impacts the LSK compartment mimicking functional and molecular defects observed in the GATA2 deficiency patients.

Disclosures
Delabesse: Novartis: Consultancy; Astellas: Consultancy. Pasquet: Novartis: Consultancy.
ASXL1 Mutation Cooperating with RUNX1 Mutation Further Perturbs the Differentiation of Neutrophils
Authors: He Jinping , Liu Qifa 
Published: November 2021

Abstract
Acute myeloid leukemia(AML) is characterized by an accumulation of myeloid progenitors. This disease can be caused by various germline mutations, including runx1 and asxl1. Recently several reports showed that mutations of ASXL1 and RUNX1 tend to coexist in AML patients. However, the impact on hematopoiesis remained uncertain. Thus far, lack of an animal model was the main limitation to study the function of the double mutations. In this work, we studied the combination role of runx1 and asxl1 by establishing a novel in vivo zebrafish model. First, we identified the characterization of 6646 patients with myeloid maliganacies in the cbioprotal database. Second, we generated a zebrafish model with double mutations by crossing the ENU-induced runx1 mutant and the CRISPR-CAS9 edited asxl1 mutant. Our results showed that truncation was the most frequent mutation type in RUNX1-mutated patients(56.3%) and ASXL1-mutated patients(87.8%). Besides, the median survival time of patients carrying double mutations was shorter than those with single RUNX1 mutation(9.61 months vs. 16.06 months ) or single ASXL1 mutation(9.61 months vs. 14.47 months). In zebrafish models, we found that the pu.1(myeloid precursor marker) positive cells increased while the gata1(proerythrocyte marker) didn't change in double mutants . Furthermore, mpo and lyz (neutrophil marker) positive cells further reduced while mpeg1 and mfap4(monocyte marker) positive cells didn't show significant difference in double mutants.Overall, we demonstrated that ASXL1 mutation cooperating with RUNX1 mutation further impeded the differentiation of the myeloid progenitors into mature neutrophils and it possibly explained the cause for a worse prognosis of patients with double mutations.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Prophylactic Administration of Antibodies Specific for the HPA-1a Epitope Prevents Alloimmunization and Platelet Destruction in a Murine Model of Fetal Neonatal Alloimmune Thrombocytopenia
Authors: Zhi Huiying , Sheridan Douglas , Newman Peter J. 
Published: November 2021

Abstract
Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder caused by maternal alloantibodies directed against paternally inherited antigens present on the surface of fetal and neonatal platelets. The human platelet alloantigen HPA-1a (formerly known as the Pl A1 alloantigen), is the most frequently implicated HPA for causing FNAIT in Caucasians. A single Leu33Pro amino acid polymorphism near the amino terminus of the integrin b3 subunit (known as GPIIIa in the platelet literature) serves as the central target for alloantibody binding, leading to clearance of both fetal and neonatal platelets, thrombocytopenia, and in the most severe cases, spontaneous- or trauma-induced intracranial hemorrhage. Unlike hemolytic disease of the newborn, which occurs in pregnancies subsequent to parturition-induced alloimmunization, an estimated 25% to 50% of FNAIT cases occur without warning during gestation of the first pregnancy. Though long proposed, there are currently no approved therapies for the prevention of FNAIT. We recently described the development of transgenic mice expressing the human HPA-1a allogeneic epitope on a murine GPIIIa backbone. Transfusion of such platelets into wild-type female mice induced the generation of high-titer anti-HPA-1a alloantibodies that can cross the placenta and recapitulate many of the relevant clinical features of FNAIT. To test the hypothesis that rapid elimination of fetal HPA-1a positive platelets from the circulation of a mother who is HPA-1a negative might prevent maternal alloimmunization and the development of FNAIT, we administered either a hyperimmune plasma-derived polyclonal anti-HPA-1a antibody derived from females having previous cases of FNAIT (termed RLYB211), or a novel human monoclonal antibody directed against the HPA-1a epitope (termed RLYB212), to wild-type female mice prior to challenging them with HPA-1a-positive murine platelets. RLYB211 and RLYB212 were each able to effect the rapid removal of HPA-1a-positive platelets from murine circulation and prevent the development of anti-HPA-1a alloantibodies. Importantly, wild-type female mice pretreated with RLYB211 prior to exposure to HPA-1a-positive platelets, and then impregnated by HPA-1a-positive males, gave birth to HPA-1a-positive pups with significantly improved platelet counts and no bleeding symptoms. These preclinical data establish the potential for prophylactic polyclonal and monoclonal anti-HPA-1a antibody therapy for the prevention of FNAIT in humans.

Disclosures
Sheridan: Rallybio: Current Employment, Current equity holder in publicly-traded company. Newman: Rallybio: Consultancy, Research Funding.
Notch Ligand Jagged1 Is a Fetal Liver Niche Factor for the Function of Embryonic Hematopoietic Stem Cells
Authors: Pajcini Kostandin V. , Shao Lijian , Paik Na Yoon , Sottoriva Kilian 
Published: November 2021

Abstract
Embryonic hematopoietic stem cells (HSC) expand rapidly during development in the fetal liver. Notch1 is required for emergence of the definitive hematopoietic stem cells (HSCs) from the hemogenic endothelium, and is essential for survival and function of HSCs in the fetal liver. The identity of the ligand and the ligand-presenting cell during hematopoietic development would provide valuable information of the Notch signaling mechanism in HSCs as well as the identity of key niche cells that drive the expansion and cell fate decisions of embryonic HSCs. In the present study, we have taken a comprehensive approach to determine the ligands and cells that initiate Notch signaling in the mouse fetal liver. To this end, we have performed single-cell analysis for all Notch signaling proteins and many known targets in E14.5 fetal HSCs and adult bone marrow HSCs as well as fetal liver endothelial cells. We determined that Jagged1 (Jag1) is highly expressed in both endothelial cells as well as in fetal HSCs but not in adult HSCs. We have performed conditional loss-of-function analysis of Jag1 in fetal endothelial cells as well as in fetal hematopoietic lineages, where both myeloid and megakaryocytic progenitors are shown to express high levels of Jag1. Our results indicate that while loss of endothelial Jag1 has severe effects in embryonic vascular development, loss of hematopoietic Jag1 allows for normal fetal morphology, yet severely impedes the functional ability of fetal liver HSCs to expand and differentiate. RNA-Sequencing analysis of long-term fetal HSCs in Jag1-mutant embryos (VavCreJag f/f) revealed reduced expression of Gata2, Mllt3, Hoxa7, Angpt1 and IL-12a genes in fetal HSCs, which are well-known regulators of self-renewal and expansion. Our findings indicate that Jag1 is an essential niche factor for development of HSCs in the fetal liver and for functional potential of fetal HSCs once in the bone marrow microenvironment.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.