bluuebunny/crossref_metadata_2025_split huggingface dataset:
Runx1 Is Strictly Required for Cbfb-MYH11 Induced Leukemia Development
Authors: Zhen Tao , Kwon Erika Mijin , Hyde R. Katherine , Zhao Ling , Lopez Guadalupe , Alemu Lemlem , Liu Pu Paul 
Published: October 2019

Abstract
Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia (AML M4Eo), which generates a CBFB-MYH11 fusion gene. The prevailing hypothesis for the mechanism of leukemia development by CBFbeta-SMMHC, the fusion protein encoded by CBFB-MYH11, is that CBFbeta-SMMHC is a dominant negative repressor of RUNX1, a transcription factor that physically interacts with CBFbeta and CBFbeta-SMMHC. If this hypothesis is correct, reducing RUNX1 activity should facilitate leukemogenesis by CBFB-MYH11. In fact, loss-of-function mutations in RUNX1 are common in human AML, but not in inv(16) AML. However, we previously demonstrated that CBFB-MYH11 has RUNX1-repression independent functions (Hyde et al., Blood 115:1433, 2010). Moreover, we recently showed that a dominant negative allele of Runx1, Runx1-lz, delayed leukemogenesis by CBFB-MYH11 in a mouse model (Hyde et al., Leukemia 29:1771, 2015). These findings challenge the RUNX1-repression model for CBFbeta-SMMHC mediated leukemogenesis. However, our previous findings are not conclusive since the Runx1+/lz mice used in the previous study have one wild-type Runx1 allele, and still retain some Runx1 function.
To definitively address this question, we crossed Cre-based conditional Runx1 knockout mice (Runx1f/f) with Cre-based conditional Cbfb-MYH11 knockin mice (Cbfb+/56M) and Mx1-Cre mice to generate Runx1f/f, Mx1-Cre, Cbfb+/56Mmice, which express CBFbeta-SMMHC but not Runx1 after pIpC (poly I:C) treatment to induce Cre expression. Runx1f/f, Mx1-Cre, Cbfb+/56Mmice had more severe platelet deficiencies and higher numbers of Lin-/Sca1-/C-kit+ progenitors and Lin-/Sca1+/C-kit+ hematopoietic stem cells in the bone marrow when comapred with Runx1f/f, Mx1-Cre mice. Unexpectedly Runx1f/f, Mx1-Cre, Cbfb+/56Mmice also developed severe macrocytic anemia within two weeks after pIpC induction, which was lethal in about 1/3 of the mice. However, none of the Runx1f/f, Mx1-Cre, Cbfb+/56M mice developed leukemia up to one year after pIpC treatment. In contrast, all Mx1-Cre, Cbfb+/56M mice developed leukemia with an average survival of 4 months, as reported previously. These results suggest that Runx1 is strictly required for Cbfb-MYH11 induced leukemogenesis.
To further study the mechanism of leukemogenesis, we performed RNA-Seq on C-kit+ bone marrow cells isolated from mice two weeks after pIpC treatment, to explore the global gene expression changes caused by Runx1 knockout on Cbfb-MYH11 expressing mice. Our preliminary data analysis showed that 1688 genes were differential expressed (Padj ≤0.05, FC ≥ 2) between Runx1f/f, Mx1-Cre, Cbfb+/56M and Mx1-Cre, Cbfb+/56M mice. Interestingly, many of these genes (48%) are Runx1 target genes. The above results suggest that mis-regulating the expression of Runx1 target genes contributes to leukemogenesis by CBFbeta-SMMHC.

Disclosures
No relevant conflicts of interest to declare.
Peptidomimetic Blockade of MYB in Acute Myeloid Leukemia
Authors: Ramaswamy Kavitha , Forbes Lauren , Brown Fiona C , Koche Richard , Gindin Tatyana , Minuesa Gerard , Kharas Michael G. , Krivtsov Andrei , Armstrong Scott A. , Still Eric , de Stanchina Elisa , Isenhart Randi , Guo Guangwu , Knoechel Birgit , Kentsis Alex 
Published: October 2019

Abstract
Aberrant gene expression is a hallmark of acute leukemias. However, therapeutic strategies for its blockade are generally lacking, in large part due to the pharmacologic challenges of drugging transcription factors. MYB-driven gene trans-activation with CREB-binding protein (CBP) is required for the initiation and maintenance of a variety of acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a prototypical peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP complex at μM concentrations and rapidly accumulates in the nuclei of AML cells. We found that treatment of AML cells with MYBMIM, but not with its inactive near-isosteric analogue TG3, led to the displacement and dissociation of MYB:CBP complex in cells, causing rapid downregulation of MYB-dependent gene expression including MYC and BCL2 oncogenes. This was associated with obliteration of H3K27Ac-driven oncogenic enhancers induced by CBP and enriched for MYB binding sites (Figure 1A; p=1e-118). Both human MLL-rearranged and non-rearranged AML cells, but not normal CD34+ umbilical cord blood progenitor cells, underwent sustained mitochondrial apoptosis in response to MYBMIM treatment, an effect that could be partially blocked by ectopic expression of BCL2. We observed that MYBMIM treatment (50 mg/kg/day) impeded leukemia progression and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells (Figure 1B; p=3.8e-3). These findings emphasize the exquisite dependence of human AML on MYB:CBP transcriptional dysregulation, and establish a pharmacologic approach for its therapeutic blockade.
Figure MYBMIM blocks oncogenic gene expression (A) and impedes leukemogenesis in vivo(B). Figure. MYBMIM blocks oncogenic gene expression (A) and impedes leukemogenesis in vivo(B).

Disclosures
Armstrong: Epizyme, Inc: Consultancy; Vitae Pharmaceuticals: Consultancy; Imago Biosciences: Consultancy; Janssen Pharmaceutical: Consultancy.
Identification of TRA-1-60-Positive Cells As a Potent Refractory Population in Follicular Lymphomas
Authors: Takata Katsuyoshi , Iioka Hidekazu , Miyata-Takata Tomoko , Miki Yukari , Yoshino Tadashi , Maeda Yoshinobu , Saito Ken , Steidl Christian , Kondo Eisaku 
Published: October 2019

Abstract
Despite receiving Rituximab-combined chemotherapy, approximately half of follicular lymphoma (FL) patients suffer tumor recurrence, a major clinical issue. Retrieval of lymphoma stem-like cells from these poorly understood, intractable lymphomas would thus greatly ameliorate the cancer therapeutics. Here we demonstrate that the TRA-1-60-expressing cells are a unique population in FLs, converge to the conventional stem cell marker Oct3/4 and ALDH1-positive population, and strongly resist current agents against B-cell lymphomas.
TRA-1-60 expression was detected in minor populations of resting B-lymphocytes inside germinal centers in reactive lymphoid tissue, whereas scattered TRA-1-60-expressing cells were detected in the marginal area of neoplastic follicles of FLs, close to small blood vessels. Translocation t(14;18) was thus detected in DNAs from the TRA-positive cells in all five patients' samples, which evinced the identical pattern of gene fusion as that of TRA-negative cells in the same tissue in 4 of 5 fresh frozen FL samples. Retrospective histological comparison between the recurrent and cognate primary tissues revealed that the number of TRA-1-60-positive lymphoma cells from R-CHOP treated FL subjects had increased four-fold relative to primary tissue, a finding corroborated by in vitro assay on Rituximab treated 2 cell lines, wherein TRA-positive cell numbers increased over ten to thirty-fold compared to the untreated sample. Moreover, TRA-1-60-positive cell population was markedly resistant to current therapeutic agents for B-cell lymphomas. Concordantly, small numbers of TRA-1-60-positive cells implanted subcutaneously into NOD/SCID mice evinced potent tumor-initiating capacity in vivo, where tumors were twelve-fold larger in volume (p=0.0021<0.005) and thirteen-fold heavier in weight (p=0.0015<0.005) compared to those xenografted from the TRA-negative cells.
In conclusion, while further investigation for molecular insights will be necessary, it is now clear that TRA-1-60 should be a prominent focus among cellular markers in follicular lymphoma research, by which we ultimately hope to explain clinical intractability against combination-Rituximab and other therapies, and to better understand the stemness among a range of lymphoma cell types.

Disclosures
Maeda: Mundipharma KK: Research Funding.
Methotrexate-Cytarabine-Dexamethasone Combination Chemotherapy with or without Rituximab in Patients with Primary Central Nervous System Lymphoma
Authors: Liu Jing , Sun Xuefei , Bai Xueyan , Chen Yuedan , Qian Jun , Zhu Hong , Wang Yaming , Ji Nan , Sun Shengjun , Wang Yajie , Liu Yuanbo 
Published: October 2019

Abstract
High-dose methotrexate (HD-MTX) based chemotherapy is the standard treatment for patients with newly diagnosed primary central nervous system lymphoma (PCNSL). The role of rituximab is controversial because as a large protein limits its penetration to blood brain barrier (BBB). We aimed to investigate the efficacy and tolerability of adding rituximab to methotrexate-cytarabine-dexamethasone combination therapy (RMAD regimen). We retrospectively analyzed 60 immunocompetent patients with newly diagnosed PCNSL from Beijing Tiantan Hospital, Capital Medical University. Twenty-four patients received 3-6 courses of methotrexate 3.5 g/m2 on day 1, cytarabine 0.5-1 g/m2 on day 2 and dexamethasone 5-10 mg on days 1, 2 and 3. Thirty-six patients received the same combination plus rituximab 375 mg/m2 on day 0. All patients repeated the treatment every 3 weeks. Patients who obtained a complete remission (CR) after induction chemotherapy received consolidation chemotherapy, and those with partial remission (PR), stable disease (SD) or progression disease (PD) received rescue whole brain radiotherapy (WBRT). After induction chemotherapy, patients treated with rituximab plus methotrexate-cytarabine-dexamethasone had a CR rate of 66.7%, compared with 33.3% of those treated with methotrexate-cytarabine-dexamethasone alone (p=.011). Seven anaphylaxis and 1 interstitial pneumonitis occured in patients with rituximab. The most common grade 1-3 adverse events were similar in the two groups including neutropenia, anaemia, thrombocytopenia, aminotransferases elevated and gastrointestinal reaction. None of the patients in the two groups experienced any grade 4 toxicity. On multivariate analysis, rituximab was associated with longer progression-free survival (PFS, hazard ratio: 5.23, 95% CI: 1.64-16.70, p=.005). Elevated serum lactate dehydrogenase (LDH) was associated with shorter OS (hazard ratio: 0.06, 95% CI: 0.00-0.97, p=.048) and PFS (hazard ratio: 0.10, 95% CI: 0.03-0.37, p=.001). HD-MTX based chemotherapy with rituximab had a higher rate of CR, and without serious toxicity. PFS but not OS benefited from addition of rituximab. LDH as an independent prognostic factor which predicted poor outcome.

Disclosures
No relevant conflicts of interest to declare.
Cytopenia, Predisposition to Myelodysplastic Syndrome, Immunodeficiency, and Neurological Disease Caused By Gain-of-Function SAMD9L Mutations Is Frequently Ameliorated By Hematopoietic Revertant Mosaicism
Authors: Tesi Bianca , Davidsson Josef , Voss Matthias , Holmes Timothy , Ripperger Tim , Chiang Samuel , Nilsson Lars , Nordenskjöld Magnus , Henter Jan-Inge , Bryder David , Fioretos Thoas , Uusimaa Johanna , Komulainen-Ebrahim Jonna , Möttönen Merja , Niinimäki Riitta , Moilanen Jukka , Rahikkala Elisa , Tedgård Ulf , Cammenga Jörg , Bryceson Yenan 
Published: October 2019

Abstract
Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic diseases characterized by impaired hematopoiesis and progression to acute myeloid leukemia (AML). Although rare, several monogenic causes of familial MDS/AML have recently been molecularly defined. We studied two families with variable manifestation of cytopenia, MDS with cytogenetic aberrations involving chromosome 7, immunodeficiency, and neurologic disease consistent with ataxia-pancytopenia syndrome.
Genetic studies uncovered heterozygous missense variants (p.Arg986Cys and p.Ile891Thr) in SAMD9L, a tumor suppressor gene located on chromosome 7. Consistent with a gain-of-function effect, transfection and over-expression of both SAMD9L variants decreased cell proliferation relative to wild-type protein. In the two families, a total of 10 individuals heterozygous for either SAMD9L mutation were identified. Three individuals developed MDS, with monosomy 7 or der(1;7)(q10;p10) as cytogenetic aberrations that encompassed the mutant SAMD9L locus. In an additional five individuals, three of which experienced a spontaneously resolved cytopenic episodes in infancy, we detected mosaic copy-neutral loss of heterozygosity of 7q by uniparental disomy, with loss of the mutated allele, or mosaic cis SAMD9L mutations. By digital PCR, we identified these events in hematopoietic progenitor cell populations, which were further enriched in B and NK cell lineages. Absent in non hematological tissues, these mutations thus represented somatic revertant mosaicism. Clinically, revertant mosaicism was associated with reduced disease severity, although in two individuals neurological manifestations persisted. Of note, two unaffected carriers without revertant mosaicism harbored an additional rare in trans germline SAMD9L p.Thr233Asn missense variant. In cellular assays, the SAMD9L p.Thr233Asn variant increased proliferation, indicating a loss-of-function effect that potentially compensates for the SAMD9L p.Arg986Cys mutation.
Together, our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause a disease with cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with chromosome 7 aberrations, where hematopoietic revertant mosaicism is common and ameliorates the clinical presentation.

Disclosures
Fioretos: Cantargia: Equity Ownership.
Observations on Chimpanzees after Whole-Body Radiation and Homologous Bone Marrow Treatment
Authors: ROTHBERG HARVEY , BLAIR EUGENE B. , GOMEZ ALPHONSE C. , MCNULTY WILBUR 
Published: October 2019

Abstract
1. Three chimpanzees were given 900 r of whole body radiation followed by transfusion of homologous bone marrow. One animal survived for nearly six months.
2. Five chimpanzees were given 1200 r of whole body radiation; three of them were given homologous bone marrow. There was no difference in survival time of treated animals and of controls.
3. Observations were made on clinical, hematologic, bacteriologic and pathologic aspects of acute radiation injury.
4. There was no evidence of a "take" of the homologous marrow. The significance of the findings is discussed.
Plasmoptysis and Gelation of Erythrocytes in Coagulation of Blood of Freshwater Bony Fishes
Authors: WOLF KEN 
Published: October 2019

Abstract
1. A clot-like material which results from very rapid plasmoptysis and hydrophyllic swelling of karyoplasm of erythrocytes from freshwater fish was reported. This attribute was found to a lesser degree in erythrocytes from an amphibian, but it was almost lacking in those of an aquatic reptile.
2. Rapid clotting of fish blood with the usual clinical methods was confirmed in this work. Fish blood clotted more quickly with the slide test than with the capillary tube test. In the presence of water, complete coagulation of fish blood occurred in only 65 per cent of the time required for clotting to be completed in air. This speed is attributed to the water-erythrocyte reaction, and not to a quality of the plasma.
3. An attempt was made to correlate the findings with the need for hemostasis and blood coagulation that is peculiar to aquatic vertebrates.
The Utilization of Protoporphyrin 9 in Heme Synthesis
Authors: GRINSTEIN MOISES , BANNERMAN ROBIN M. , MOORE CARL V. 
Published: October 2019

Abstract
The experiments described in this communication demonstrate that C14-tagged protoporphyrin 9 can be incorporated into the heme during the biosynthesis of hemoglobin.
1. In vitro observations:
(a) C14 protoporphyrin 9 was found to be incorporated into heme by hemolysates of chicken and human blood incubated at 37 C. The degree of incorporation by washed chicken erythrocytes was less, presumably because the protoporphyrin was not readily transferred across the cell membrane. Incorporation by hemolysates was inhibited completely at 1 x 10-2 M KCN at 4 C., markedly by 1 x 10-2 M KCN at 37 C. and partially by 1 x 10-3 M Pb at 37 C.
(b) The degree of incorporation was reduced by the addition of an equivalent quantity of delta-aminolevulinic acid. Furthermore, the incorporation of glycine-2-C14 into heme was reduced by the addition of an equivalent quantity of protoporphyrin 9.
2. In vivo observations:
Intravenously administered C14 protoporphyrin was incorporated into the circulating hemoglobin of two rabbits with a phenylhydrazine-induced hemolytic anemia.
These observations provide support for the view that protoporphyrin 9 itself is a true direct precursor of hemoglobin, in the biosynthetic pathway between porphobilinogen and heme. Comparative studies of rates of incorporation of C14 protoporphyrin 9 and its precursors into heme in vitro may provide a useful tool for the study of heme synthesis in normal and pathologic conditions. For instance, it was shown that hemolysates from the blood of patients with thalassemia major, with poor iron and glycine utilization, rapidly incorporated the tagged protoporphyrin into heme.
Multiple Inherited Erythrocyte Abnormalities in an American Negro Family: Hereditary Spherocytosis, Sickling and Thalassemia
Authors: COHEN FLOSSIE , ZUELZER WOLF W. , NEEL JAMES V. , ROBINSON ABNER R. 
Published: October 2019

Abstract
An American Negro family has been described in which there are found the genes responsible for three inherited abnormalities of the erythrocyte, namely, the genes resulting in spherocytosis, a thalassemia-like trait and the sickling phenomenon. The study of this family provides evidence for the independent segregation of the genes responsible for this type of thalassemia and the sickling phenomenon, and for spherocytosis and the sickling phenomenon. It is noteworthy that the thalassemia gene present in this family is not associated with an increased proportion of hemoglobin A2, and fails to exhibit "factor interaction" with the sickle cell gene, and the question is raised whether these attributes characterize a type of thalassemia gene non-allelic to the sickle cell gene.
Lymph Node Reactivity. II. Fetal Lymph Nodes
Authors: BLACK MAURICE M. , SPEER FRANCIS D. 
Published: October 2019

Abstract
A study was made of the progressive development of structure and metalophilia of the axillary nodes obtained from fetuses of various weights. Metalophil cells were rare in fetuses weighing less than 1000 Gm., while the adult pattern of metalophilia was not observed until the fetus approached 2000 Gm. The findings were discussed in terms of their relationships to perinatal death.
Detection of Leukocyte Antibodies by the Complement Consumption Test
Authors: CHUDOMEL V. , JEZKOVA Z. , LIBANSKY J. 
Published: October 2019

Abstract
A new method for the demonstration of leukocyte antibodies by the complement consumption test is described. For this test active serum and the complement of the examined serum itself is used. In the presence of antibodies against the antigen used, complement consumption takes place during the antigen-antibody reaction. This consumption can be estimated while titrating C' by the difference between the first completely hemolyzed test tube in the lower row (serum to which no antigen had been added), and the test tube with complete hemolysis in the upper row (serum with added antigen).
Two hundred-eighty normal sera, 105 sera of patients suffering from variouts internal diseases and 78 sera from patients with disorders of the blood were examined. The complement consumption test gave positive results more often than did the leukoagglutination method.
The method described was also successful in the demonstration of thrombocyte antibodies. We believe that it is equally suited for the detection of various tissue antibodies.
A Method for the Measurement of Red Cell Dimensions and Calculation of Mean Corpuscular Volume and Surface Area
Authors: HOUCHIN DONALD N. , MUNN JOHN I. , PARNELL BENJAMIN L. 
Published: October 2019

Abstract
Houchin, D. N., Munn, J. I., and Parnell, B. L.: A method for the measurement of red cell dimensions and calculation of mean corpuscular volume and surface area. Blood 13:1185-1191, 1958.
Page 1186: the formula for surface area (ninth line from the bottom of the page) should read:
See PDF for Equation
Dysproteinemia Induced in Vitro by Plasmin Digestion of Fibrinogen
Authors: KOWALSKI E. , BUDZYŃSKI A. , KOPEC M. , MURAWSKI K. 
Published: October 2019

Abstract
1. Electrophoretic investigation of split products of plasmin digestion of pure fibrinogen and of fibrinogen in a plasma medium was performed. It was shown that split products possessed electrophoretic mobilities of alpha, beta and gamma globulins.
2. It could be shown that by digestion of I131-labeled fibrinogen, radioactivity in the range of alpha, beta and gamma globulins is released.
3. Simultaneously with the formation of high molecular intermediates, low molecular, TCA-soluble substances are released.
4. Radioactivity balance calculation of the relative amounts of the newly formed fractions has been performed.
5. A possible influence of plasmin-induced fibrinogen proteolysis on the electrophoretic pattern of plasma proteins in dysproteinemia has been suggested.
6. The electrophoretic pattern of plasma proteins, obtained in the above experiments is similar to those seen in patients with dysproteinemia.
Neonatal Neutropenia Due to Maternal Isoimmunization
Authors: LALEZARI PARVIZ , NUSSBAUM MURRAY , GELMAN SIDNEY , SPAET THEODORE H. 
Published: October 2019

Abstract
A family is reported with multiple cases of neonatal neutropenia. The first child died of severe infection, the second was asymptomatic, the third and the fourth children had a benign course of agranulocytosis which lasted about 10 weeks and was followed by spontaneous recovery. A potent leukoagglutinin was found in the maternal serum which agglutinated leukocytes obtained from the father and all three available children but failed to agglutinate the mother’s own cells. Identical leukoagglutinin was found in the last baby’s serum; it disappeared after the baby recovered. The disorder is tentatively named "isoimmune neonatal neutropenia" and is considered to represent a condition analogous to erythroblastosis fetalis.
Brief Note: Hemoglobin J in a Healthy Hawaiian-Chinese-Caucasian Male
Authors: JIM ROBERT T. S. , YARBRO MARINA T. 
Published: October 2019

Abstract
Hemoglobin J is reported in a 27 year old healthy adult Hawaiian-Chinese-Caucasian male and 3 of his offspring. All were healthy and displayed no hematologic disturbances except for the Youngest offspring, who exhibited mild nutritional iron deficiency anemia.