Infection Exposure Is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5-Inherited...
Plasmodium infection promotes genomic instability and AID-dependent B cell lymphoma. Cell 2015;162:727-37. ... Proliferation Assay. Ba/F3 cells (2 × 105) expressing either murine Jak3WT, Jak3R653H, or the empty vector control were washed ... we transfected IL3-dependent Ba/F3 cells with the murine Jak3R653H variant and observed cytokine-independent growth (Fig. 4D), ... Childhood B-cell precursor acute lymphoblastic leukemia (pB-ALL) is the most common cancer in childhood. The overall cure rate ...http://cancerdiscovery.aacrjournals.org/content/5/12/1328.long
Non-classical karyotypic features in relapsed childhood B-cell precursor acute lymphoblastic leukemia - Zurich Open Repository...
Karyotype analysis of acute lymphoblastic leukemia (ALL) at diagnosis has provided valuable prognostic markers for treatment stratification. However, reports of cytogenetic studies of relapsed ALL samples are limited. We compared the karyotypes from 436 nonselected B-cell precursor ALL patients at initial diagnosis and of 76 patients at first relapse. We noticed a relative increase of karyotypes that did not fall into the classic ALL cytogenetic subgroups (high hyperdiploidy, t(12;21), t(9;22), 11q23, t(1;19), ,45 chromosomes) in a group of 29 patients at relapse (38%) compared to 130 patients at presentation (30%). Non-classical cytogenetic aberrations in these 29 patients were mostly found on chromosomes 1, 2, 7, 9, 13, 14, and 17. We also describe six rare reciprocal translocations, three of which involved 14q32. The most frequent abnormalities were found in 9p (12/29 cases) and were associated with a marked decrease in the duration of ...http://www.zora.uzh.ch/id/eprint/26136/
Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute...
Despite risk-adapted treatment, survival of children with relapse of acute lymphoblastic leukemia (ALL) remains poor compared with that of patients with initial diagnosis of ALL. Leukemia-associated genetic alterations may provide novel prognostic factors to refine present relapse treatment strategies. Therefore, we investigated the clinical relevance of 13 recurrent genetic alterations in 204 children treated uniformly for relapsed B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. The most common alterations were deletions of CDKN2A/2B, IKZF1, PAX5, ETV6, fusion of ETV6-RUNX1 and deletions and/or mutations of TP53. Multivariate analysis identified IKZF1 deletion and TP53 alteration as independent predictors of inferior outcome (P=0.002 and P=0.001). Next, we investigated how both alterations can improve the established risk stratification in relapsed ALL. Intermediate-risk relapse patients with low minimal ...https://epub.uni-regensburg.de/30572/
Intrachromosomal amplification of chromosome 21 in Korean pediatric patients with B-cell precursor acute lymphoblastic leukemia...
The patients in this study showed similar clinical features, as compared with previous reports on iAMP21. Patients with iAMP21 comprised 3.4% of pediatric BCP-ALL patients in this study, which was concordant with 2% in other studies. Other features of iAMP21 such as the presence of a low WBC count and older age at initial diagnosis were also observed. None of the patients were under three years of age. None of the patients showed a WBC count above 50×109/L. In this study, two of 10 cases (20%) showed replacement of a normal chromosome 21 with an abnormal marker chromosome. Four of 10 patients (40%) showed normal karyotype. iAMP21 patients with normal karyotype varied from 0%  to 43%  in other reports, which could be mainly due to the difference in specimen quality and detection sensitivity of each test.. Some findings in this study have not been clearly described in previous reports. There were significantly more SER in the iAMP21 patient group than in the no iAMP21 patient group. Most ...http://www.bloodresearch.or.kr/journal/view.html?uid=2050&vmd=Full
GSI-I (Z-LLNle-CHO) inhibits γ-secretase and the proteosome to trigger cell death in precursor-B acute lymphoblastic leukemia
PubMed Central Canada (PMC Canada) provides free access to a stable and permanent online digital archive of full-text, peer-reviewed health and life sciences research publications. It builds on PubMed Central (PMC), the U.S. National Institutes of Health (NIH) free digital archive of biomedical and life sciences journal literature and is a member of the broader PMC International (PMCI) network of e-repositories.http://pubmedcentralcanada.ca/pmcc/articles/PMC3170956/?lang=en-ca
NIH Clinical Center: NIH Clinical Center Senior Staff
ORIGINAL ARTICLES. Davis, B.H., Holden, J.T., Bene, M.D., Borowitz, M.J., Braylan, R.C. Cornfield, D., Gorczyca, W., Lee, R. Maiese, R, Orfao, A., Wells, D., Wood, B. L., Stetler-Stevenson, M. 2006 Bethesda International Consensus Recommendations on the Flow Cytometric Immunophenotypic Analysis of Hematolymphoid Neoplasia: Medical Indications. Cytometry B Clin Cytom. 2007 72B:S13.. Al-Quran SZ, Yang L, Magill JM, Braylan RC, Douglas-Nikitin VK. Assessment of bone marrow plasma cell infiltrates in multiple myeloma: the added value of CD138 immunohistochemistry. Hum Pathol. 2007;38(12):1779-87.. Lee RV, Braylan RC, Rimsza LM. CD58 expression decreases as nonmalignant B cells mature in bone marrow and is frequently overexpressed in adult and pediatric precursor B-cell acute lymphoblastic leukemia. Am J Clin Pathol. 2005;123(1):119-24.. Braylan RC. Impact of flow cytometry on the diagnosis and characterization ...https://clinicalcenter.nih.gov/about/SeniorStaff/raul_braylan.html
FDA approves new treatment for adults with relapsed or refractory acute lymphoblastic leukemia - Healthcanal.com : Healthcanal...
The U.S. Food and Drug Administration today approved Besponsa (inotuzumab ozogamicin) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).. "For adult patients with B-cell ALL whose cancer has not responded to initial treatment or has returned after treatment, life expectancy is typically low," said Richard Pazdur, M.D., director of the FDA's Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "These patients have few treatments available and today's approval provides a new, targeted treatment option.". B-cell precursor ALL is a rapidly progressing type of cancer in which the bone marrow makes too many B-cell lymphocytes, an immature type of white blood cell. The National Cancer ...https://www.healthcanal.com/cancers/leukemia/239967-fda-approves-new-treatment-adults-relapsed-refractory-acute-lymphoblastic-leukemia.html
Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like...
PRIMARY OBJECTIVES:. I. To determine if the administration of post-Induction age-adjusted intrathecal triple therapy (ITT) on a Modified Berlin-Frankfurt-Munster (MBFM) interim maintenance high-dose methotrexate (IMHDM) backbone will improve 5-year disease-free survival (DFS) of children with high-risk (HR) B-acute lymphoblastic leukemia (ALL) compared to age-adjusted intrathecal (IT) methotrexate (MTX).. II. To determine, in a randomized fashion, if the cyclophosphamide + etoposide containing regimen (Experimental Arm 1) will improve the 4-year DFS of children, adolescents, and young adults with very high-risk (VHR) B-ALL compared to a modified MBFM-IMHDM regimen that contains a second IM (Control Arm).. SECONDARY OBJECTIVES:. I. To determine the toxicity and tolerability of post-Induction age-adjusted ITT compared to age-adjusted IT MTX in children with HR B-ALL.. II. To determine the toxicity and tolerability of Experimental Arm 1 compared to the Control Arm in children, ...https://clinicaltrials.gov/ct2/show/record/NCT02883049?show_desc=Y
FDA Approves Blincyto (blinatumomab) For Use In Pediatric Patients With Philadelphia Chromosome-Negative Relapsed Or Refractory...
Blincyto (blinatumomab) is used to treat pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Includes Blincyto side effects, interactions and indications.https://www.drugs.com/newdrugs/fda-approves-blincyto-blinatumomab-pediatric-patients-philadelphia-chromosome-negative-relapsed-4426.html
Research: Scientific Publications | cnio.es
Ribera J, Zamora L, Morgades M, Mallo M, Solanes N, Batlle M, Vives S, Granada I, Juncà J, Malinverni R, Genescà E, Guàrdia R, Mercadal S, Escoda L, Martinez-Lopez J, Tormo M, Esteve J, Pratcorona M, Martinez-Losada C, Solé F, Feliu E, Ribera JM; Spanish PETHEMA Group; Spanish Society of Hematology. (2017). Copy number profiling of adult relapsed B-cell precursor acute lymphoblastic leukemia reveals potential leukemia progression mechanisms. Gene Chromosome Canc 56, 812-820 ...https://www.cnio.es/ing/publicaciones/publicaciones.asp?pagina=16
Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor...
Despite the favorable prognosis of childhood acute lymphoblastic leukemia (ALL), a substantial subset of patients relapses. As this occurs not only in the high risk but also in the standard/intermediate groups, the presently used risk stratification is suboptimal. The underlying mechanisms for treatment failure include the presence of genetic changes causing insensitivity to the therapy administered. To identify relapse-associated aberrations, we performed single-nucleotide polymorphism array analyses of 307 uniformly treated, consecutive pediatric ALL cases accrued during 1992-2011. Recurrent aberrations of 14 genes in patients who subsequently relapsed or had induction failure were detected. Of these, deletions/uniparental isodisomies of ADD3, ATP10A, EBF1, IKZF1, PAN3, RAG1, SPRED1 and TBL1XR1 were significantly more common in B-cell precursor ALL patients who relapsed compared with those remaining in complete remission. In univariate ...http://umu.diva-portal.org/smash/record.jsf?pid=diva2:709077
Standard Risk B-precursor Acute Lymphoblastic Leukemia. - AdisInsight
This phase III trial is assessing the efficacy, tolerability and quality-of-life effects of induction therapy with cytarabine + vincristine + dexamethasone +http://adisinsight.springer.com/trials/700003653
The synergism of MCL1 and glycolysis on pediatric acute lymphoblastic leukemia cell survival and prednisolone resistance |...
In vitro and in vivo resistance to prednisolone are predictive for an adverse prognosis in pediatric precursor-B acute lymphoblastic leukemia. Causes of resistance are still poorly understood. In this study, we observed that prednisolone exposure of prednisolone-sensitive patients' leukemic cells decreased anti-apoptotic MCL1 protein levels by 2.9-fold, while MCL1 protein expression in prednisolone-resistant leukemic patients cells was unaffected (p,0.01). Locked nucleic acid oligonucleotides directed against MCL1 (MCL1 LNA) reduced MCL1 protein levels by 82 +/- 16% (p,0.05) in leukemic cells, decreased proliferation by 9-fold and sensitized to prednisolone up to 80.8-fold, compared to a non-silencing-control LNA (p,0.05). Remarkably, we discovered that MCL1-silencing upregulated the glucose consumption of leukemic cells by 2.5-fold (p,0.05), suggesting a potential rescue ...http://www.haematologica.org/content/early/2013/10/04/haematol.2013.093823
Both mature KIR+ and immature KIR- NK cells control pediatric acute B cell precursor leukemia in NOD.Cg-Prkdcscid IL2rgtmWjl/Sz...
Therapeutic natural killer (NK) cell-mediated alloreactivity towards acute myeloid leukemia (AML) has largely been attributed to mismatches between killer immunoglobulin-like receptors (KIRs) on NK cells and their ligands, HLA class I molecules, on target cells. While adult acute B cell precursor leukemia (BCP-ALL) appears to be resistant to NK cell-mediated lysis, recent data indicate that pediatric BCP-ALL might yet be a target of NK cells. We here demonstrate in a donor-patient-specific NOD.Cg-Prkdc(scid) IL2rg(tmWjl)/Sz (NSG) xenotransplantation model that NK cells mediate considerable alloreactivity towards pediatric BCP-ALL in vivo. Notably, not only adoptively transferred mature, KIR(+) NK cells but also immature, KIR- NK cells arising early post transplantation in humanized NSG mice (huNSG) exerted ...http://www.zora.uzh.ch/id/eprint/101934/
Acute B Lymphoblastic Leukemia (B-ALL) | Flow Cytometry
The incidence of acute leukemia is approximately 4 cases per 100,000 per year. 30% of these are ALL. ALL is generally seen in children 75% of cases are usually in children under 6 years of age. There are approximately 3200 cases of ALL in the United States per year; 80-85% of these are precursor B-ALL, the others are precursor T-ALL. The overall cure rate in children is 85%, and about 50% of adults have long-term disease-free survival.. ...http://clinicalflow.com/acute-b-lymphoblastic-leukemia-b-all
Overexpression Of Tyrosine Kinase And Chromatin Remodeling Genes In The IAMP21 Subtype Of Pediatric Acute Lymphoblastic Leukemia
Intrachromosomal amplification of chromosome 21 (iAMP21) is a cytogenetic subtype associated with relapse and poor prognosis in pediatric B-cell precursor acut...https://www.omicsonline.org/proceedings/overexpression-of-tyrosine-kinase-and-chromatin-remodeling-genes-in-the-iamp21-subtype-of-pediatric-acute-lymphoblastic--68121.html
Combination Chemotherapy in Treating Children With Stage III or Stage IV Non-Hodgkin's Lymphoma or Acute Lymphoblastic...
OBJECTIVES: I. Evaluate the feasibility and toxicity of dose intensification of methotrexate and cyclophosphamide in patients with stage III or IV small, noncleaved cell non-Hodgkin's lymphoma or B cell acute lymphoblastic leukemia. II. Estimate the response rate and survival of these patients after this therapy.. OUTLINE: This is a two-stage study. Patients will receive cytarabine either by continuous infusion (first stage) or bolus injection (second stage). Patients are stratified by disease (stage III non-Hodgkin's lymphoma (NHL) vs stage IV NHL vs stage B acute lymphoblastic leukemia). Therapy for all patients consists of alternating courses of 'A' and 'B'. Patients with stage III disease receive 4 courses of chemotherapy (ABAB) while those with stage IV disease and B cell acute lymphoblastic leukemia receive 6 ...https://clinicaltrials.gov/ct2/show/NCT00003217
Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like...
During the early phases (phases 1 and 2), researchers assess safety, side effects, optimal dosages and risks/benefits. In the later phase (phase 3), researchers study whether the treatment works better than the current standard therapy. They also compare the safety of the new treatment with that of current treatments. Phase 3 trials include large numbers of people to make sure that the result is valid. There are also less common very early (phase 0) and later (phase 4) phases. Phase 0 trials are small trials that help researchers decide if a new agent should be tested in a phase 1 trial. Phase 4 trials look at long-term safety and effectiveness, after a new treatment has been approved and is on the market. ...http://www.mayo.edu/research/clinical-trials/cls-20152035
The Mechanisms of HOXA9-Mediated Oncogenic Transformation
Abstract: Hox genes encode a family of homeodomain-containing transcription factors that are critical for body plan specification and tissue morphogenesis during embryonic development. Hoxa9, in particular, is required for adult hematopoiesis in which it promotes stem cell renewal and expansion. Most importantly, Hoxa9 is commonly dysregulated in various types of acute leukemia, including acute myeloid leukemia (AML), and T- and B-precursor acute lymphoblastic leukemia (B-ALL and T-ALL). Together with its co-factor MEIS1, HOXA9 plays a causal role in driving leukemic transformation. Hoxa9 dysregulation is also linked to various types of solid tumors, and both gain and loss of function have been implicated in tumorigenesis. Despite its central role, the mechanism through which HOXA9 mediates oncogenic transformation remains poorly understood. Previous work in our lab found that in a HOXA9/MEIS1-driven AML ...https://deepblue.lib.umich.edu/handle/2027.42/138797
Expression of miR-196b is not exclusively MLL-driven but is especially linked to activation of HOXA genes in pediatric acute...
The expression of miR-196b was measured in 72 pediatric ALL cases at diagnosis. Figure 1 shows that miR-196b was highly expressed in nine out of 12 MLL-rearranged ALL cases and in 14 out of 22 cases of T-ALL. In particular, all CALM-AF10 (n=5), MLL-AF6 (n=2), SET-NUP214 (n=3) and inv(7) (n=1) positive T-ALL cases showed high levels of expression of miR-196b comparable to the levels found in MLL-rearranged cases (Figure 1). Since these specific chromosomal abnormalities are linked to the activation of HOXA genes19,20 and since miR-196b is mapped between HOXA9 and HOXA10, we quantified the expression of the HOXA9 and HOXA10 transcripts by RT-qPCR. A strong correlation between the level of expression of miR-196b and HOXA9 and HOXA10 expression (Rs ≥ 0.7; P≤0.005) was found in MLL-rearranged precursor B-ALL as well as in cases of T-ALL (Figure 2). Figure 2 and Online Supplementary Figure S1 illustrate that patients with low levels of expression of miR-196b (such as non-MLL ...http://www.haematologica.org/content/95/10/1675
Jonathan M. Ducore, M.D., M.P.H. for UC Davis Health
Syvanen M, Ducore J. Whole genome comparisons reveals a possible chimeric origin for a major metazoan assemblage. Journal of Biological Systems, (18) 261-75. 2010. Zunino SJ, Storms DH, Ducore JM. Novel in vivo model of inducible multi-drug resistance in acute lymphoblastic leukemia with chromosomal translocation t(4;11). Cancer Lett. 2010 Oct 1;296(1):49-54. Epub 2010 Apr 9.. Zunino SJ, Storms DH, Ducore JM. Parthenolide treatment activates stress signaling proteins in high-risk acute lymphoblastic leukemia cells with chromosomal translocation t(4;11). Int J Oncol. 2010 Nov;37(5):1307-13.. Gofman I, Ducore JM. Risk Factors for the Development of Obesity in Children Surviving ALL and NHL. Journal of Pediatric Hematologyl Oncology, 31(2): 101-107. 2008. Zunino SJ, Ducore JM, Storms DH. Parthenolide induces significant apoptosis and production of reactive oxygen species in high-risk pre-B leukemia ...http://www.ucdmc.ucdavis.edu/publish/facultybio/search/271/
Leicester Research Archive: Involvement of ID4 (Inhibitor of DNA Binding 4) in Haematopoietic Malignancies
Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus have been described in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). One of these, t (6;14)(p22;q32), involved the Inhibitor of DNA Binding 4 (ID4) gene, resulting in deregulated ID4 expression. Members of the ID family are helix-loop-helix proteins that lack DNA binding domains. They are thought to regulate cellular differentiation and proliferation by binding and sequestering E proteins from their DNA targets. The aim of this thesis was to examine the expression and oncogenic potential of ID4 in B-cells. ID4 expression was detected in a subset of chronic lymphocytic leukaemia (CLL) and BCP-ALL lacking the ID4/IGH chromosomal translocation. ID4 expression defined a subtype of BCP-ALL with a distinctive gene signature. ID4, unlike other members of the ID family is not expressed in normal B-cells. ...https://lra.le.ac.uk/handle/2381/9506
ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here, we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ...http://cancerres.aacrjournals.org/content/early/2017/08/02/0008-5472.CAN-17-0701
Increased Th17 cells and IL-17A exist in patients with B cell acute lymphoblastic leukemia and promote proliferation and...
Immune regulation is crucial for the pathogenesis of B-cell acute lymphoblastic leukemia (B-ALL). It has been reported that Th17 cells as a newly identified subset of CD4+ T cells are involved in the pathogenesis of several hematological disorders. However, the role of Th17 cells in the pathophysiology of B-ALL is still unclear. The frequencies of T cells were determined by flow cytometry in the peripheral blood and bone marrow of 44 newly diagnosed B-ALL patients and 25 age-matched healthy donors. The cell viability and apoptosis were determined by CCK-8 assay and Annexin V staining, respectively. Western blot was applied to identify the level of Akt and Stat3 phosphorylation. We assessed and observed a significantly increased frequency of Th17 cells and a drastically decreased frequency of Th1 cells in peripheral blood mononuclear ...https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-016-0894-9
PAX5 - SNPedia
The protein known as Paired box protein Pax-5 is encoded by the PAX5 gene; it is a member of the paired box (PAX) family of transcription factors.Wikipedia rs398123063(A), a rare variation known as c.547G,A or Gly183Ser, has been associated with autosomal dominant B cell precursor acute lymphoblastic leukemia (B-ALL). Individuals carrying this variation appear to require the deletion or inactivation of their normal allele at this locus to develop clinical symptoms of B-ALL.[PMID 24013638] ...https://www.snpedia.com/index.php/PAX5