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leukemia, minimal residual disease, genetic variation

Małgorzata Dawidowska, Maria Kosmalska, Łukasz Sędek, Aleksandra Szczepankiewicz, Magdalena Twardoch, Alicja Sonsala, Bronisława Szarzyńska-Zawadzka, Katarzyna Derwich, Monika Lejman, Katarzyna Pawelec, Agnieszka Obitko-Płudowska, Katarzyna Pawińska-Wąsikowska, Kinga Kwiecińska, Andrzej Kołtan, Agnieszka Dyla, Władysław Grzeszczak, Jerzy R Kowalczyk, Tomasz Szczepański, Ewa Ziętkiewicz, Michał Witt
Minimal residual disease (MRD) enables reliable assessment of risk in acute lymphoblastic leukemia (ALL). However, little is known on association between MRD status and germline genetic variation. We examined 159 Caucasian (Slavic) patients with pediatric ALL, treated according to ALL-IC-BFM 2002/2009 protocols, in search for association between 23 germline polymorphisms and MRD status at day 15, day 33 and week 12, with adjustment for MRD-associated clinical covariates. Three variants were significantly associated with MRD: rs1544410 in VDR (MRD-day15); rs1051266 in RFC (MRD-day33, MRD-week12), independently and in an additive effect with rs10519613 in IL15 (MRD-day33)...
2016: Scientific Reports
Jizhong Liu, Ashish Masurekar, Suzanne Johnson, Sohini Chakraborty, John Griffiths, Duncan Smith, Seema Alexander, Clare Dempsey, Catriona Parker, Stephanie Harrison, Yaoyong Li, Crispin Miller, Yujun Di, Zhumur Ghosh, Shekhar Krishnan, Vaskar Saha
Despite the high cure rates in childhood acute lymphoblastic leukemia (ALL), relapsed ALL remains a significant clinical problem. Genetic heterogeneity does not adequately explain variations in response to therapy. The chemoprotective tumor microenvironment may additionally contribute to disease recurrence. This study identifies metabolic reprogramming of leukemic cells by bone marrow stromal cells (BMSC) as a putative mechanism of drug resistance. In a BMSC-extracellular matrix culture model, BMSC produced chemoprotective soluble factors and facilitated the emergence of a reversible multidrug resistant phenotype in ALL cells...
December 15, 2015: Oncotarget
Thomas Smol, Olivier Nibourel, Alice Marceau-Renaut, Karine Celli-Lebras, Céline Berthon, Bruno Quesnel, Nicolas Boissel, Christine Terré, Xavier Thomas, Sylvie Castaigne, Hervé Dombret, Claude Preudhomme, Aline Renneville
EVI1 overexpression confers poor prognosis in acute myeloid leukemia (AML). Quantification of EVI1 expression has been mainly assessed by real-time quantitative PCR (RT-qPCR) based on relative quantification of EVI1-1D splice variant. In this study, we developed a RT-qPCR assay to perform quantification of EVI1 expression covering the different splice variants. A sequence localized in EVI1 exons 14 and 15 was cloned into plasmids that were used to establish RT-qPCR standard curves. Threshold values to define EVI1 overexpression were determined using 17 bone marrow (BM) and 31 peripheral blood (PB) control samples and were set at 1% in BM and 0...
December 2015: Leukemia Research
Yishai Ofran, Jacob M Rowe
PURPOSE OF REVIEW: Acute myeloid leukemia (AML) is a heterogeneous disease. Detection of minimal residual disease (MRD) has the potential to improve risk stratification, and its routine monitoring may allow timely therapeutic actions such as allogeneic hematopoietic stem cell transplantation. The current review will discuss challenges and available evidence for clinical application of MRD detection in AML management. RECENT FINDINGS: The heterogeneous nature of AML, variations in genetic aberrations and immunophenotypes among patients and between malignant subclones coexisting within a single patient, is a challenge for the development of a reliable MRD test in AML...
March 2015: Current Opinion in Hematology
Nicolas Gendron, Nabila Belhouachi, Véronique Morel, Zahia Azgui, Karim Maloum, Florence Nguyen-Khac, Jean-Michel Cayuela, Frédéric Davi, Hélène Merle-Béral, Elise Chapiro
We report here the case of a sixty-eight-year old woman with chronic myeloid leukemia. Molecular techniques identified the presence of the rare e19a2 BCR-ABL1 transcript. The patient was treated by 1(st) generation tyrosine-kinase inhibitor (TKI) (imatinib). Disease monitoring was performed by cytogenetic analyses and quantification of the BCR-ABL1 transcript. After 3 months, the treatment was modified due to an absence of biological response and poor tolerance. After 21 months with 2nd generation TKIs (nilotinib), the patient was responding optimally to treatment, with a complete cytogenetic response and a major molecular response...
May 2014: Annales de Biologie Clinique
Nicolas Duployez, Olivier Nibourel, Alice Marceau-Renaut, Christophe Willekens, Nathalie Helevaut, Aurélie Caillault, Céline Villenet, Karine Celli-Lebras, Nicolas Boissel, Eric Jourdan, Hervé Dombret, Martin Figeac, Claude Preudhomme, Aline Renneville
Although acute myeloid leukemia (AML) with t(8;21) belongs to the favorable risk AML subset, relapse incidence may reach 30% in those patients. RUNX1-RUNX1T1 fusion transcript is a well-established marker for minimal residual disease (MRD) monitoring. In this study, we investigated the feasibility and performances of RUNX1-RUNX1T1 DNA as MRD marker in AML with t(8;21). In 17/22 patients with t(8;21)-positive AML treated in the French CBF-2006 trial, breakpoints in RUNX1 and RUNX1T1 were identified using long-range PCR followed by next-generation sequencing...
June 2014: American Journal of Hematology
Hans B Ommen, Peter Hokland, Torsten Haferlach, Lotte Abildgaard, Tamara Alpermann, Claudia Haferlach, Wolfgang Kern, Susanne Schnittger
Correct action upon re-emergence of minimal residual disease in acute myeloid leukaemia (AML) patients has not yet been established. The applicability of demethylating agents and use of allogeneic stem cell transplantation will be dependent on pre-relapse AML growth rates. We here delineate molecular growth kinetics of AML harbouring MLL partial tandem duplication (MLL-PTD; 37 cases) compared to those harbouring MLL translocations (43 cases). The kinetics of MLL-PTD relapses was both significantly slower than those of MLL translocation positive ones (median doubling time: MLL-PTD: 24 d, MLL-translocations: 12 d, P = 0·015, Wilcoxon rank sum test), and displayed greater variation depending on additional mutations...
June 2014: British Journal of Haematology
W Zeijlemaker, J W Gratama, G J Schuurhuis
Detection of minimal residual disease is recognized as an important post-therapy risk factor in acute myeloid leukemia patients. Two most commonly used methods for residual disease monitoring are real-time quantitative polymerase chain reaction and multiparameter flow cytometry. The results so far are very promising, whereby it is likely that minimal residual disease results will enable to guide future post-remission treatment strategies. However, the leukemic clone may change between diagnosis and relapse due to the instability of the tumor cells...
January 2014: Cytometry. Part B, Clinical Cytometry
Susanne Radtke, Oliver Zolk, Bertold Renner, Marios Paulides, Martin Zimmermann, Anja Möricke, Martin Stanulla, Martin Schrappe, Thorsten Langer
The pharmacogenetics of methotrexate (MTX) was investigated in a large cohort of pediatric patients with acute lymphoblastic leukemia (ALL). Four hundred ninety-nine children with ALL from the ALL-BFM (Berlin-Frankfurt-Münster) 2000 trial who received 1996 courses of MTX at 5 g/m(2) were genotyped for 8 single nucleotide polymorphisms in 5 candidate genes of the MTX/folate pathway. Patients' MTX pharmacokinetics, MTX toxicities, and outcomes were correlated with the genotypes. The interindividual variability in MTX kinetics had a substantial genetic component between 68% and 75%...
June 27, 2013: Blood
Lixia Zhang, Qinghua Li, Wei Li, Bingcheng Liu, Ying Wang, Dong Lin, Chunlin Zhou, Chengwen Li, Jianxiang Wang, Yingchang Mi
The fusion gene AML1/ETO is a molecular marker for monitoring minimal residual disease (MRD) in acute myeloid leukemia with the t(8;21)(q22;q22) translocation. To evaluate the dynamic variation and prognostic significance of AML1/ETO, bone marrow samples from 52 patients at different periods were examined qualitatively (32 patients) or quantitatively (20 patients) using nested RT-PCR and RQ-PCR, respectively. In the qualitative group, AML1/ETO in 71.88 and 95.45 % patients became negative at six and 24 months after CR, respectively...
June 2013: International Journal of Hematology
Jun J Yang, Cheng Cheng, Meenakshi Devidas, Xueyuan Cao, Dario Campana, Wenjian Yang, Yiping Fan, Geoff Neale, Nancy Cox, Paul Scheet, Michael J Borowitz, Naomi J Winick, Paul L Martin, W Paul Bowman, Bruce Camitta, Gregory H Reaman, William L Carroll, Cheryl L Willman, Stephen P Hunger, William E Evans, Ching-Hon Pui, Mignon Loh, Mary V Relling
With the use of risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the past 40 years. However, a substantial portion of patients, many of whom have no known risk factors, experience relapse. Taking a genome-wide approach, in the present study, we evaluated the relationships between genotypes at 444 044 single nucleotide polymorphisms (SNPs) with the risk of relapse in 2535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen...
November 15, 2012: Blood
A Wesolowska, M D Dalgaard, L Borst, L Gautier, M Bak, N Weinhold, B F Nielsen, L R Helt, K Audouze, J Nersting, N Tommerup, S Brunak, T Sicheritz-Ponten, H Leffers, K Schmiegelow, R Gupta
Genetic variants, including single-nucleotide polymorphisms (SNPs), are key determiners of interindividual differences in treatment efficacy and toxicity in childhood acute lymphoblastic leukemia (ALL). Although up to 13 chemotherapeutic agents are used in the treatment of this cancer, it remains a model disease for exploring the impact of genetic variation due to well-characterized cytogenetics, drug response pathways and precise monitoring of minimal residual disease. Here, we have selected clinically relevant genes and SNPs through literature screening, and on the basis of associations with key pathways, protein-protein interactions or downstream partners that have a role in drug disposition and treatment efficacy in childhood ALL...
June 2011: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Chumphorn Banklau, Sumalee Jindadamrongwech, Ruchchadol Sawangpanich, Suntaree Apibal, Suradej Hongeng, Karan Paisooksantivatana, Samart Pakakasama
BACKGROUND: Single nucleotide polymorphisms (SNPs) of deoxycytidine kinase (dCK) and cytidine deaminase (CDA) are known to alter their enzymatic activities, which affect the metabolism of cytarabine. Currently, treatment of childhood acute lymphoblastic leukemia (ALL) includes cytarabine, especially in high-risk patients. Therefore, we hypothesized that a genetic variation of dCK and CDA genes may influence the risk of cytarabine-related toxicities and early response to treatment. PATIENTS AND METHODS: We included children diagnosed with ALL and lymphoblastic lymphoma (LL) stage III and IV...
2010: Hematology/oncology and Stem Cell Therapy
Deepa Bhojwani, Scott C Howard, Ching-Hon Pui
Although most children with acute lymphoblastic leukemia (ALL) are cured, certain subsets have a high risk of relapse. Relapse risk can be predicted by early response to therapy, clinical and pharmacogenetic features of the host, and genetic characteristics of leukemic cells. Though early treatment response can be assessed by the peripheral blast cell count after 1 week of single-agent glucocorticoid treatment or percent of bone marrow blasts by morphology after 1 or 2 weeks of multiagent induction treatment, determination of minimal residual disease by polymerase chain reaction (PCR) or flow cytometry after 2 to 6 weeks of induction is the most precise and useful measure...
2009: Clinical Lymphoma & Myeloma
Jun J Yang, Cheng Cheng, Wenjian Yang, Deqing Pei, Xueyuan Cao, Yiping Fan, Stanley B Pounds, Geoffrey Neale, Lisa R Treviño, Deborah French, Dario Campana, James R Downing, William E Evans, Ching-Hon Pui, Meenakshi Devidas, W P Bowman, Bruce M Camitta, Cheryl L Willman, Stella M Davies, Michael J Borowitz, William L Carroll, Stephen P Hunger, Mary V Relling
CONTEXT: Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response. OBJECTIVES: To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy...
January 28, 2009: JAMA: the Journal of the American Medical Association
Michael J Borowitz, Meenakshi Devidas, Stephen P Hunger, W Paul Bowman, Andrew J Carroll, William L Carroll, Stephen Linda, Paul L Martin, D Jeanette Pullen, David Viswanatha, Cheryl L Willman, Naomi Winick, Bruce M Camitta
Minimal residual disease (MRD) is an important predictor of relapse in acute lymphoblastic leukemia (ALL), but its relationship to other prognostic variables has not been fully assessed. The Children's Oncology Group studied the prognostic impact of MRD measured by flow cytometry in the peripheral blood at day 8, and in end-induction (day 29) and end-consolidation marrows in 2143 children with precursor B-cell ALL (B-ALL). The presence of MRD in day-8 blood and day-29 marrow MRD was associated with shorter event-free survival (EFS) in all risk groups; even patients with 0...
June 15, 2008: Blood
Ya-zhen Qin, Jin-Lan Li, Hong-Hu Zhu, Ling-Di Li, Yan Chang, Hao Le, Guo-Rui Ruan, Yan-Rong Liu, Xiao-Jun Huang, Shan-Shan Chen
OBJECTIVE: To evaluate levels of common specific fusion transcripts M-bcr-abl, m-bcr-abl, TEL-AML1, AML1-ETO, PML-RAR alpha, CBF beta-MYH11 in untreated leukemia patients. METHODS: Specific fusion transcript levels were detected by TaqMan-based real-time quantitative RT-PCR technique in a total of 208 samples, including 195 bone marrow samples from 50 M-bcr-abl(+) chronic phase-chronic myeloid leukemia (CML-CP), 10 M-bcr-abl(+) acute lymphoblastic leukemia (ALL), 19 m-bcr-abl(+) ALL, 11 TEL-AML1(+) ALL, 30 AML1-ETO(+) acute myeloid leukemia (AML), 58 PML-RAR alpha(+) acute promyelocytic leukemia (APL) and 17 CBF beta-MYH11(+) AML patients and 13 peripheral blood samples from 13 M-bcr-abl(+) CML-CP patients...
July 2007: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Marina I Gutiérrez, Georgina Timson, Abdul K Siraj, Rong Bu, Shakuntala Barbhaya, Sripad Banavali, Kishor Bhatia
t(9;22) generates the BCR-ABL fusion gene, the hallmark of chronic myeloid leukemia (CML) but also found in acute lymphoblastic leukemia (ALL). Multiple chimeric transcripts translate to proteins of 190 or 210 kd and, rarely, 230 kd. CML typically carries p210 BCR-ABL while ALL is most often associated with p190. Detection and quantification of these fusion transcripts is useful in clinical management. We have exploited the unique melting profiles of these transcripts to design a new, simple, and cost-effective assay based on monochrome multiplex real-time RT-PCR for identification and quantification of each of these transcripts (b3-a2, b2-a2, and e1-a2) without further manipulation...
February 2005: Journal of Molecular Diagnostics: JMD
H Leroy, S de Botton, N Grardel-Duflos, S Darre, X Leleu, C Roumier, F Morschhauser, J-L Lai, F Bauters, P Fenaux, C Preudhomme
Despite the favorable prognosis of patients with acute myeloid leukemia (AML) with t(8;21)(q22;q22) translocation, relapses still occur in about 30% of the cases but no initial factors can strongly predict the risk of relapse. Several recent studies suggest that monitoring minimal residual disease (MRD) may identify patients at risk of relapse. We prospectively monitored AML1-ETO rearrangement by real-time quantitative PCR (RQ-PCR) in 21 patients uniformly treated in our center. Blood (PB) and bone marrow (BM) samples were collected during and after therapy...
March 2005: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Bradley T Messmer, Emilia Albesiano, Dimitar G Efremov, Fabio Ghiotto, Steven L Allen, Jonathan Kolitz, Robin Foa, Rajendra N Damle, Franco Fais, Davorka Messmer, Kanti R Rai, Manlio Ferrarini, Nicholas Chiorazzi
Previous studies suggest that the diversity of the expressed variable (V) region repertoire of the immunoglobulin (Ig)H chain of B-CLL cells is restricted. Although limited examples of marked constraint in the primary structure of the H and L chain V regions exist, the possibility that this level of restriction is a general principle in this disease has not been accepted. This report describes five sets of patients, mostly with unmutated or minimally mutated IgV genes, with strikingly similar B cell antigen receptors (BCRs) arising from the use of common H and L chain V region gene segments that share CDR3 structural features such as length, amino acid composition, and unique amino acid residues at recombination junctions...
August 16, 2004: Journal of Experimental Medicine
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