bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone Marrow (BM) Minimal Residual Disease (MRD) at End of Induction and Interim Maintenance Is Highly Predictive of Outcome in Children with Standard Risk (SR) Acute Lymphoblastic Leukemia (ALL) Treated on the Children’s Oncology Group Study 1991
Authors: Matloub Yousif , Gaynon Paul S. , Jayabose Somasundaram , Bostrom Bruce C. , Hunger Stephen P. , Angiolillo Anne L , Devidas Meenakshi , Linda Stephen , Carroll William L. , Winick Naomi , Sather Harland , Pine Sharon R 
Published: October 2019

Abstract
Three thousand fifty four children with NCI SR ALL were enrolled on CCG-1991; 2075 eligible patients were randomized and began treatment with intrathecal cytarabine, vincristine (V), dexamethasone (DX), and pegylated asparaginase (ASP). Bone marrow status was assessed at Day 7 and 14, and 28 of Induction. Slow early responders (SER’s) (Day 7/14 M3-M3, or M3-M2; and M2 at Day 28 Induction) received rescue daunorubicin and were assigned to augmented BFM therapy (N Engl J Med1998; 338:1663). Other patients were designated rapid early responders (RER’s) and randomly allocated to V/ intravenous methotrexate versus oral 6MP/oral methotrexate, and DX pulses in months 3–4 and 7–8 of therapy and single or double delayed intensification. The 5-year EFS for RER’s and SER’s was 90.5% (SE ± 1.0%) and 84.7% (SE = ±3.7%). Eight hundred three patients elected to participate in a companion study of minimal residual disease (MRD), which was successfully performed on BM samples of 750 patients (93.4%). Out of 1362 BM submitted samples, 1360 were successfully tested. MRD was assessed by real-time quantitative PCR of clone-specific immunoglobulin heavy chain, immuno-globulin kappa deleting element, and T-cell receptor gene rearrangements on Day 14 Time Point (TP #1) for patients not achieving M1 status at Day 7, end Induction (TP #2) and Day 84 (RER’s) or Day 119 (SER’s) (TP #3), i.e., Day 28 of Interim Maintenance). Various levels of MRD positivity were explored for prognostic significance (see Table). At TP’s 1, 2, and 3, 14%, 57%, and 78% had undetectable MRD with sensitivity of 0.01% or better. At the three time points patients with detectable MRD were 2.7 to 4.3 times more likely to fail than patients with undetectable MRD. TP #1, however, unlike TP #2 and TP #3 was not predictive of EFS in our study. Patients who had MRD > 0.01% at TP#1 had a much lower EFS at 4 years if at TP #3 MRD persisted at > 0.01% vs ≤ 0.01% (78 ± 0.1% vs 94 ± 0.05%, p = 0.01). We assessed MRD by PCR at three TP’s in a homogeneous population of children with SR ALL receiving V/ DX/ASP. At end of induction, 57% of patients were MRD negative but still accrued 1/3 of adverse events.
Time Point 1 Time Point 2 Time Point 3 MRD Day 14 (Induction Day 14) Day 28 (RER) or 35 (SER) (End Induction) Day 84 (RER) or 119 (SER) (Interim Maintenance Day 28) *Sensitivity < 0.01% “absolute” negative* 1/44 13/340 15/350 low positive < 0.01% 1/27 8/89 5/50 positive 0.01 %–0.1% 6/87 6/104 3/37 positive 0.1%–1% 6/91 4/43 4/9 positive > 1% 6/67 7/21 1/1 total 20/316 45/597 30/448
The POZ/BTB Domain Transcription Factor Miz-1 (Zbtb17) Is Required during Early B Cell Development for the Survival of B-Cell Progenitors and Is Essential for the Formation of Mature Follicular B Cells
Authors: Kosan Christian , Moroy Tarik 
Published: October 2019

Abstract
B-cell development takes place in the bone marrow and is defined by a number of sequential steps that include the up-regulation of CD19, the rearrangement of immunoglobulin heavy and light chain genes (V(D)J recombination) and the expression of surface immunoglobulin. The early steps are regulated by cytokine signaling and the hierarchical expression of transcription factors, among them EBF, Pax5 and E2A and any interference with these critical elements leads to partial or total abrogation of B cell development. Here we present evidence that the POZ/BTB domain transcription factor Miz-1 (Zbtb17) represents an important novel regulator of the early development of follicular B cells. We have used gene targeting in mice to generate a non-functional allele of Miz-1 in all hematopoietic cells. In these mice, the development of adult follicular B cells is almost entirely abrogated, whereas the formation of marginal zone B-cells remain unaffected. Miz-1 deficiency correlated with the absence of CD19+ pro B-cells from the bone marrow and a block at the transition of the pre-pro-B cell to the pro-B cell stage. Although common lymphoid progenitors (CLPs) that are at the origin of B-cell development were present in Miz-1 deficient mice, they showed decreased expression of E2A, EBF and Pax5 compared to their wild type counterparts. Moreover, they were unable to differentiate in culture into more mature B cells even on stroma cells (OP9) and the presence or absence of IL-7. Interestingly, a forced expression of EBF or PAX5 in Miz-1 deficient progenitor cells did not rescue this phenotype. Furthermore, fetal B cell development, which has been shown to depend on EBF and Pax5, is not altered in Miz-1 deficient mice, suggesting that Miz-1 acts in a pathway that is independent of these critical B-cell regulators. In contrast, however, to EBF and Paxc5, the co-expression of a Bcl-2 transgene almost completely restored the development of more mature CD19+ or IgM+ B-cells in Miz-1 deficient mice. This indicated that Miz-1 is implicated in the regulation of cell survival at early stages of B cell development. Since it has been shown before that Bcl-2 is a downstream effector of Miz-1, it is conceivable that Miz-1 regulates Bcl-2 in the early B cell precursors, possibly as an element of the IL-7 signaling pathway, and thereby ensures their survival and proper development. We conclude that Miz-1 represents a novel regulator of early B cell development that exerts its function at a precise step in adult mice independently of other well-established regulators of B-cell development such as EBF or Pax5.
The Rho GTPase Cdc42 is essential for B lyphocyte development and Activation
Authors: Guo Fukun , Zheng Yi 
Published: October 2019

Abstract
Cdc42 of the Rho GTPase family has been implicated in a wide range of fundamental cell functions including actin cytoskeleton dynamics, proliferation, and migration, but its cell-type specific functions have just begun to be appreciated. Previous studies of Cdc42 in B cell regulation by using dominant mutant forms of Cdc42 suggest that Cdc42 is involved in B cell cytoskeleton organization and antigen-receptor signaling, however, its contribution to the B-lineage development and B cell physiology remains unknown. In this study we have achieved B cell- and hematopoietic stem cell-deletion of cdc42 by conditional gene targeting with the CD19 and Mx promoter-driven Cre expression, respectively, in the cdc42loxP/loxP mice. Deletion of cdc42 after the pre-proB cell stage significantly inhibited late B cell development, resulting in reduced mature B cell populations in spleen, bone marrow, peripheral blood, lymph node, and peritoneal cavity. Accordingly, antigen-specific IgM, IgG1 and IgG3, was reduced in the Cdc42-deificient mice. The reduction of Cdc42 knockout B cells are associated with impaired proliferation and survival. Cdc42 deficiency caused a BCR signaling defect with increased Erk and decreased Akt activation, and a defect in BCR-mediated BAFF receptor upregulation and subsequent BAFF receptor signaling in the mature resting B cells. Interestingly, Cdc42 is dispensable for SDF-1α- or BLC-induced B cell migration. Further, deletion of Cdc42 from hematopoietic stem cells resulted in an unaltered common lymphoid progenitor production but severely reduced pre-proB/proB/preB and immature B cell populations, indicating that Cdc42 is also critically involved in the B cell precursor differentiation. Together our results reveal multi-facet roles of Cdc42 in B cell development and activation.
Early Consolidation with Myeloablative Radiochemotherapy Followed by Autologous Stem Cell Transplantation in First Remission in Mantle Cell Lymphoma: Long Term Follow up of a Randomized Trial of the
Authors: Dreyling Martin H. , Hoster Eva , Van Hoof Achiel , Metzner Bernd , Gisselbrecht Christian , Pfreundschuh Michael , Reiser Marcel , Truemper Lorenz H. , Steinhauer Hjalmar , Boiron Jean-Michel , Boogaerts Marc , Silingardi Vittorio , Nelemans J.C. Kluin- , Unterhalt Michael , Hiddemann Wolfgang 
Published: October 2019

Abstract
Background: Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma with an especially poor prognosis and a median survival of only 3–4 years.
Methods: In 1996, the European MCL Network initiated a randomized trial to improve the dismal outcome of MCL, comparing early consolidation with myeloablative radiochemotherapy (TBI 12 gray, cyclophosphamide 120 mg/kg bw) followed by autologous stem cell transplantation (ASCT) to a conventional α-interferon maintenance (6×106 IE IFN- α3x weekly) in first remission after a CHOP-like induction regimen (Dreyling et al, Blood 2005). Here we report the long term results of this prospective trial.
Results: Until March 2004, a total of 232 previously untreated patients up to 65 years with advanced stage MCL were randomized upfront. 173 (76%) of 228 patients evaluable according to the intention to treat (ITT) responded to initial induction chemotherapy and 151 of these (87%) proceeded to the assigned consolidation therapy. 144 patients were evaluable per protocol, 75 pts in the ASCT arm and 69 patients in the IFN maintenance arm. Baseline characteristics were comparable in the per protocol as well as in the ITT cohorts. Patients in the ASCT study arm experienced a significantly longer response duration (RD, median 3.7 years) as compared to patients in the IFNa arm (median 1.6 years, p = 0.0004). These differences were even more pronounced in the CR patients (median response duration 4.5 years vs. 1.6 years) and the intent to treat analysis (median time to treatment failure 2.6 vs. 1.4 years, p = 0.0001). Most importantly, this advantage resulted in a pronounced trend towards an improved overall survival (OS) in the ASCT arm. After a prolonged follow-up of up to 10 years (median 6.1 years), median survival after ASCT was 7.5 years in comparison to 5.4 years under IFN-α maintenance (p = 0.075). In the intent to treat analysis median OS was 7.5 vs. 5.3 years (p = 0.031). As expected, acute toxicity was higher in the ASCT group, whereas long-term effects were more frequently encountered under IFN-α maintenance.
Conclusion: In first line treatment of advanced stage MCL, dose-intensified consolidation with myeloablative radiochemotherapy followed by ASCT after CHOP-like induction results in a significantly prolonged response duration and may also result in an improved overall survival. Accordingly, dose-intensified regimens represent the current therapeutic standard in younger MCL patients. Future study concepts will evaluate the addition of molecular targeted approaches to further improve long term outcome.
Defective Telomerase in Familial Myelodysplasia and Leukemia
Authors: Kirwan Michael , Vulliamy Tom , Walne Amanda J. , Beswick Richard , Hillmen Peter , Kelly Richard , Stewart Andrew , Bowen David , Schonland Stefan , Whittle Annika Maria , McVerry Tony , Gilleece Maria , Dokal Inderjeet 
Published: October 2019

Abstract
Myelodysplastic syndromes (MDS) comprise a diverse range of hematological conditions, all of which involve impaired or disturbed hematopoiesis, cytopenias, marrow dysplasia and the risk of progression to acute myeloid leukemia (AML). MDS and AML are believed to involve a multi-step process arising within bone marrow stem cells, but the specific defects responsible remain poorly understood. In cases of inherited, familial forms of the disease two genes have been implicated: the hematopoietic transcription factors CBFA2 (core binding factor a2) and CEBPA (CCATT box enhancer binding protein a) and these account for only a small number of the familial cases so far reported. The uncharacterized families represent an ideal resource for identifying the primary pathology of the disease. In this study we have screened 21 families where MDS/AML appears to be familial for mutations in the telomerase enzyme components TERC (telomerase RNA component) and TERT (telomerase reverse transcriptase). In two families, we have identified novel mutations in TERC and in another two we have identified mutations in TERT directly resulting in MDS/AML. Functional analysis has demonstrated that all mutations adversely impact telomerase activity in vitro and affected individuals have short telomeres (see Table 1 for summary). These results have several important implications: First, they identify a novel genetic pathway (defective telomere maintenance) that can lead to familial MDS/AML; second, they suggest that TERC and TERT act as tumour suppressors and; finally, they have implications for the biology, treatment and screening regimen for de novo cases of MDS/AML.
Family Number of affected individuals Mutation Telomerase activity compared to wild type Age-adjusted telomere length 1 3 TERC c.212C>G 1% −4.62 2 5 TERC c.309G>T 4% 0.01 3 2 TERTc.1892G>A 0% −4.45 4 2 TERTc.2354C>T 11% −3.12
Table 1 – Summary of clinical and molecular analyses of four families with MDS/AML
A Common Single Nucleotide Polymorphism in the Chromosome 7q22.3 Region, Which Is Frequently Deleted in Myeloid Malignancies, Is Associated with Mean Platelet Volume and Platelet Function in Healthy Individuals
Authors: Soranzo Nicole , Tijssen Marloes R. , Rendon Augusto , Meisinger Christine , Jones Chris I. , Gieger Christian , Watkins Nicholas A. , Menzel Stephan , Prokisch Holger , Stephens Jonathan , Doering Angela , Erber Wendy N. , Potter Simon C. , Burns Philippa , Jolley Jennifer , Falchi Mario , Garner Stephen F. , Rankin Angela , Thein Swee Lay , Wichmann H-Erich , Goodall Alison H. , Illig Thomas , Spector Tim D. , Deloukas Panos , Ouwehand Willem H. 
Published: October 2019

Abstract
The variation in blood cell indices between individuals is to a large extent genetically controlled. In the normal population mean platelet volume (MPV) is inversely correlated with platelet count. We undertook a genome-wide association analysis of MPV on 2.5 million imputed genotypes in 1,475 individuals from the UK Blood Services Common Controls, followed by replication in an additional 7,098 samples from four independent collections. We identified a novel locus on chromosome 7q22.3, in a region frequently deleted in myeloid malignancies, where the lead single nucleotide polymorphism (SNP) had a highly significant association with MPV (average G allele effect size 0.15 log fl, 95% CI 0.0118–0.0174, P-value = 9.5×10−24) and an opposite effect on platelet counts (G allele effect −4.51 109/l, 95% CI −6.112 - −2.900, P-value = 1.46×10−7), but the SNP did not exert an effect on red cell indices. The lead SNP with a minor allele frequency of 0.46 is intergenic between the hypothetical gene FLJ36031 and the PIK3CG gene. There are 6 genes in the 1-Mb window centred around the lead SNP and all but HBP1 are transcribed in megakaryocytes (MKs) and to a variable degree in the other seven blood cell lineages. The formation and regulation of volume of platelets is critically dependent on the interaction of MK-expressed integrins with extracellular matrix proteins like fibrinogen and collagen. This prompted us to analyze, in our platelet function cohort of 500 healthy individuals, the association between the lead SNP and binding of both fibrinogen and annexin V to platelets following activation with the collagen mimetic CRP-XL, both associations were significant, with P-values of 0.05 and 0.003, respectively. In summary, we describe a common SNP associated with differences in volume, count and function of platelets from healthy individuals. Intriguingly, our results indicate that the same 7q22.3 region which is frequently deleted in myeloid malignancies harbours important regulatory elements of several platelet phenotypic traits.
Effects of the Mcl-1/Bcl-2 Inhibitor GX015-070 (Obatoclax®) on Growth and Viability of Canine and Human Neoplastic Mast Cells
Authors: Peter Barbara , Aichberger Karl J. , Gleixner Karoline V. , Ferenc Veronika , Gruze Alexander , Pickl Winfried F. , Willmann Michael , Valent Peter 
Published: October 2019

Abstract
Mcl-1 is a Bcl-2 family-member that has been described to act anti-apoptotic in various myeloid neoplasms. We and others have recently shown that neoplastic mast cells (MC) in patients with systemic mastocytosis (SM) display Mcl-1, Bcl-2, and Bcl-xL. In the present study, we examined the effects of the Mcl-1/Bcl-2-targeting drug GX015-070 (obatoclax®; GeminX, Montréal, Quebéc, Canada) on growth and viability of primary neoplastic MC obtained from patients with SM (n=3), the human MC leukemia cell line HMC-1, and the canine mastocytoma cell line C2. Two HMC-1 subclones, one lacking KIT D816V (HMC- 1.1) and one expressing KIT D816V (HMC-1.2) were examined. As assessed by RT-PCR and immunostaining, primary neoplastic MC as well as HMC-1 cells (both subclones) were found to express Mcl-1 mRNA and the Mcl-1 protein in a constitutive manner, but did not express significant amounts of proapoptotic Bim. Transfection of HMC-1 cells with Mcl-1-specific siRNA resulted in reduced proliferation and increased apoptosis compared to cells transfected with a control siRNA. GX015-070 was found to inhibit 3H-thymidine uptake and thus proliferation in HMC-1 cells in a dose-dependent manner, with higher IC50 values obtained in HMC-1.2 cells (0.5 μM) compared to HMC-1.1 cells (0.05 μM). GX015-070 also inhibited the growth and survival in the canine mastocytoma cell line C2 (IC50: 0.5-1 μM). Moreover, GX015-070 was found to inhibit the proliferation of primary human neoplastic MC in all SM patients tested (IC50: 0.05-0.1 μM). We next attempted to combine obatoclax with a modulator of Mcl-1/Bim expression in MC, in order to enhance drug effects. Since Bim is degraded via the proteasome, we applied the proteasome inhibitor bortezomib. Whereas GX015-07 did not modulate the production/expression of Mcl-1 or Bim in HMC-1 cells, bortezomib was found to promote the expression of Bim in our Western blot experiments. In addition, bortezomib was found to suppress 3H-thymidine uptake in both HMC-1 subclones. Finally, bortezomib was found to cooperate with GX015-070 in producing apoptosis in HMC-1.1 cells, HMC-1.2 cells, and C2 cells. Together, our data show that the Mcl-1/Bcl-2-targeting drug GX015-070 is a potent inhibitor of in vitro growth and survival of canine and human neoplastic MC. Targeting of Mcl-1 in neoplastic MC alone or in combination with a Bim-regulator may be an interesting pharmacologic approach in advanced SM.
Pomalidomide (CC4047) Plus Low-Dose Dexamethasone (Pom/dex) Is Highly Effective Therapy in Relapsed Multiple Myeloma
Authors: Lacy Martha Q. , Hayman Suzanne R. , Gertz Morie A. , Allred Jacob B. , Mandrekar Sumithra J. , Dispenzieri Angela , Zeldenrust Stephen R. , Kumar Shaji , Greipp Philip R. , Lust John A. , Russell Stephen J , Buadi Francis , Kyle Robert A. , Bergsagel Peter Leif , Fonseca Rafael , Roy Vivek , Mikhael Joseph , Stewart A. Keith , Rajkumar S. Vincent 
Published: October 2019

Abstract
Background: Thalidomide and its analogue lenalidomide have high response rates among patients with newly diagnosed as well as previously treated myeloma. Pomalidomide (CC4047) is the newest immunomodulatory (IMiD) agent that has shown single-agent activity in phase I studies. We report on the first Phase 2 trial of pomalidomide combined with low dose dexamethasone (Pom/dex) in patients with relapsed or refractory multiple myeloma.
Methods: 37 patients (21 male and 16 female) were enrolled. Pomalidomide was given orally 2 mg daily on days 1–28 of a 28-day cycle. Dexamethasone was given orally at a dose of 40 mg daily on days 1, 8, 15 and 22 of each cycle. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily as prophylaxis against DVT.
Results: The median age was 66 years (range, 40 – 88). All patients were evaluable for response and toxicity, and all analysis were done on intent to treat basis. All patients had received prior therapy; 38% had 3 prior regimens; 35% had 2 prior regimens and 27% had one prior regimen. 76% had previous autologous stem cell transplant (ASCT) and 24% had 2 prior ASCT. 62% had previous IMiD therapy. Toxicity was mild and consisted primarily of myelosuppression. Grade 3 neutropenia occurred in 31%; grade 3 thrombocytopenia 3%; grade 3 anemia 3 %. Other grade 3/4 toxicities seen in less than 5% pts included: diarrhea, atrial fibrillation, pneumonia, dehydration and renal insufficiency. 16 % had grade 1/2 neuropathy. No grade 3 neuropathy was seen and there have been no thromboembolic events. Thirty (81%) patients are continuing study treatment. Seven patients have discontinued treatment due to: disease progression (5), died on study (1) and the medical doctor’s discretion (1). Twenty three of 37 patients (62%) achieved an objective response to therapy; including 9 (24%) with VGPR; 14 patients (38%) with PR; 6 (16%) with stable disease. Objective responses were seen in 4 of 13 patients (29%) who were refractory to lenalidomide.
Conclusions: Pomalidomide plus dexamethasone (Pom/dex) is highly active and well tolerated for treatment of relapsed/refractory multiple myeloma with an objective responserate of 62%, including a 29% response rate among patients who are lenalidomiderefractory.