Leukaemias into the 21st century. Part 2: the chronic leukaemias.
Intern Med J. 2013 May;43(5):484-94
Authors: Gibson J, Iland HJ, Larsen SR, Brown CM, Joshua DE
Like the acute leukaemias, the chronic leukaemias are broadly classified according to their cell lineage of origin. Chronic myeloid leukaemia and chronic lymphocytic leukaemia are the most common disease entities within the myeloid and lymphoid lineages, although several less common entities are well recognised within each broad subgroup. In common with the dramatic progress in the acute leukaemias, there has been considerable progress in our understanding of the biology and molecular genetics of the chronic leukaemias that is now being translated into significant therapeutic advances.
PMID: 23668266 [PubMed - indexed for MEDLINE]
Incidence of bcr?abl fusion transcripts in healthy individuals.
Mol Med Rep. 2014 Feb 13;
Authors: Ismail SI, Naffa RG, Yousef AM, Ghanim MT
Bcr?abl fusion transcripts, resulting from translocation t(9;22), are hallmarks of Philadelphia chromosome positive (Ph+) leukemias. This translocation is detected in >90% of patients with chronic myelogenous leukemia and ~20% of acute lymphoblastic leukemia patients, which predominantly express the p210 and p190 proteins, respectively. Although the occurrence of t(9;22) in healthy individuals has been previously demonstrated, the number of studies is limited and the results are inconsistent. The present study screened for the presence of bcr?abl transcripts in the blood of a group of healthy individuals using a sensitive?nested reverse transcription polymerase chain reaction (RT?PCR) assay. Samples were collected from 189 healthy volunteers (145 adults and 44 children). RNA was reverse transcribed and amplified by two rounds of PCR, amplifying the two common variants of bcr?abl transcripts, p190 and p210. While the bcr?abl p190 transcript was not detected, the p210 transcript was detected in ~10% of samples. Notably, the incidence of p210 translocation was higher in males (12.2%) compared with females (7.7%) and males were 2.4 times more likely to have the translocation. A significant incidence was also observed in adults compared with children, where adults were 6 times more likely to have the translocation. The presence of bcr?abl transcripts in the blood of a significant proportion of healthy individuals should be considered in long?term investigations to establish its exact association with the risk of developing leukemia. Furthermore, the current assays should be revised to consider the proportion of normal samples carrying the p210 transcripts when making a differential diagnosis.
PMID: 24535287 [PubMed - as supplied by publisher]
Phosphorylated Crkl reduction levels are associated with the lowest P-glycoprotein activity levels in cells from chronic myeloid leukemia patients.
Leuk Res. 2013 Dec;37(12):1711-8
Authors: Vasconcelos FC, Nestal de Moraes G, Moellmann-Coelho A, Maia RC
ABCB1/P-glycoprotein (Pgp) and ABCG2/BCRP overexpression have been described as related to imatinib resistance in chronic myeloid leukemia (CML). We showed in CML cells from 55 patients that Pgp activity was more frequently detected than BCRP activity (p=0.0074). Imatinib-induced Crkl phosphorylated protein (pCrkl) reduction was more pronounced in K562 (Pgp-negative) than in K562-Lucena (Pgp-positive) CML cell line. Expressive pCrkl reduction levels after in vitro imatinib treatment was observed in samples from patients exhibiting lower Pgp activity levels compared with patients exhibiting higher Pgp activity levels (p=0.0045). Pgp activity in association with pCrkl reduction levels might help to distinguish between imatinib-resistant and imatinib-sensitive CML cells.
PMID: 24210993 [PubMed - indexed for MEDLINE]
Safety and efficacy of switching to nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on frontline imatinib or nilotinib 300 mg twice daily.
Haematologica. 2014 Feb 14;
Authors: Hughes TP, Hochhaus A, Kantarjian HM, Cervantes F, Guilhot F, Niederwieser D, le Coutre PD, Rosti G, Ossenkoppele G, Lobo C, Shibayama H, Fan X, Menssen HD, Kemp C, Larson RA, Saglio G
In a randomized, phase 3 trial of nilotinib versus imatinib in patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, more patients had suboptimal response or treatment failure on frontline imatinib than on nilotinib. Patients with suboptimal response/treatment failure on imatinib 400 mg once or twice daily or nilotinib 300 mg twice daily could enter an extension study to receive nilotinib 400 mg twice daily. After a 19-month median follow-up, the safety profile of nilotinib 400 mg twice daily in patients switching from imatinib (n = 35) was consistent with previous reports, and few new adverse events occurred in patients escalating from nilotinib 300 mg twice daily (n = 19). Of patients previously treated with imatinib or nilotinib 300 mg twice daily, respectively, 15/26 (58%) and 2/6 (33%) without complete cytogenetic response at extension study entry, and 11/34 (32%) and 7/18 (39%) without major molecular response at extension study entry, achieved these responses at any time on nilotinib 400 mg twice daily. Estimated 18-month rates of freedom from progression and overall survival after entering the extension study were lower for patients switched from imatinib (85% and 87%, respectively) versus nilotinib 300 mg twice daily (95% and 94%, respectively). Nilotinib dose escalation was generally well tolerated and improved responses in about one-third of patients with suboptimal response/treatment failure. Switch to nilotinib improved responses in some patients with suboptimal response/treatment failure on imatinib, but many did not achieve complete cytogenetic response. Clinicaltrials.gov identifiers: NCT00718263, NCT00471497 (extension).
PMID: 24532039 [PubMed - as supplied by publisher]
Resveratrol induces human K562 cell apoptosis, erythroid differentiation, and autophagy.
Tumour Biol. 2014 Feb 15;
Authors: Yan HW, Hu WX, Zhang JY, Wang Y, Xia K, Peng MY, Liu J
Resveratrol (Res) is a naturally occurring phytoalexin with apoptotic and inducing-glob effects in leukemic cells, but the potential induction of erythroid differentiation in cells is not fully understood. Here, we investigated the effects of Res on human erythro-megakaryoblastic leukemia cell line K562. Among the treated cells, proliferation was inhibited and the occurrence of cell apoptosis and cell death were detected. Erythroid differentiation assay was explored, and we found that Res could increase the expression of glycophorin A (GPA), HBA1, HBB, and ?-globin genes and enforced the expression of GPA, CD71, and Band3 proteins. Res also induced K562 cell autophagy when the concentration of Res was increased up to 50 or 100 ?M. Our findings suggested that Res possesses the potency not only inducing apoptosis but also inducing erythroid differentiation and autophagy in K562 cells. These results provide that Res may be a therapeutic candidate for chronic myelogenous leukemia treatment.
PMID: 24526417 [PubMed - as supplied by publisher]
The multidrug resistance pumps are inhibited by silibinin and apoptosis induced in K562 and KCL22 leukemia cell lines.
Leuk Res. 2013 Nov 5;
Authors: Noori-Daloii MR, Saffari M, Raoofian R, Yekaninejad M, Dinehkabodi OS, Noori-Daloii AR
Silibinin have been introduced for several years as a potent antioxidant in the field of nutraceuticals. Based on wide persuasive effects of this drug, we have decided to investigate the effects of silibinin on chronic myelogenous leukemia (CML) in vitro models, K562 and KCL22 cell lines. Lactate dehydrogenase (LDH) release, microculture tetrazolium test (MTT assay) and real-time PCR were employed to evaluate the effects of silibinin on cell cytotoxicity, cell proliferation and expression of various multidrug resistance genes in these cell lines, respectively. Our results have shown that presence of silibinin has inhibitory effects on cell proliferation of K562 and KCL22 cell lines. Also, our data indicated that silibinin, in a dose-dependent manner with applying no cytotoxic effects, inhibited cell proliferation and reduced mRNA expression levels of some transporter genes e.g. MDR1, MRP3, MRP2, MRP1, MRP5, MRP4, ABCG2, ABCB11, MRP6 and MRP7. The multifarious in vitro inhibitory effects of silibinin are in agreement with growing body of evidence that silibinin would be an efficient anticancer agent in order to be used in multi-target therapy to prevail the therapeutic hold backs against CML.
PMID: 24522246 [PubMed - as supplied by publisher]
By pass Mechanisms of Resistance to Tyrosine Kinase Inhibition in Chronic Myelogenous Leukaemia.
Curr Drug Discov Technol. 2014 Feb 11;
Authors: Marfe G, Di Stefano C
Chronic myeloid leukaemia (CML) is a disease induced by the BCR-ABL oncogene. Tyrosine kinase inhibitors (TKIs) were introduced in the late 1990s and have revolutionized the management of CML. The majority of such patients can now expect to live a normal life providing they continue to comply with TKI treatment. However, in a significant proportion of cases, TKI resistance develops over time, requiring a change of therapy. Over the past few years, multiple molecular mechanisms of resistance have been identified and some common themes have emerged. One is the development of resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective TK domain. The second is activation of alternative molecules that maintain the signalling of key downstream pathways despite sustained inhibition of the original drug target. In this mini-review, we summarize the concepts underlying resistance, the specific examples known to date and the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.
PMID: 24521199 [PubMed - as supplied by publisher]
Possible paths and potential barriers to successfully modeling drug resistance.
Future Med Chem. 2013 Jul;5(11):1181-3
Authors: Anderson AC
PMID: 23859198 [PubMed - indexed for MEDLINE]
Targeting miR-21 induces autophagy and chemosensitivity of leukemia cells.
Curr Drug Targets. 2013 Sep;14(10):1135-43
Authors: Seca H, Lima RT, Lopes-Rodrigues V, Guimaraes JE, Almeida GM, Vasconcelos MH
Overexpression of oncomiR-21 has been observed in most cancer types, such as leukemia. This miR has been implicated in a number of cellular processes, including chemoresistance, possibly by directly modulating the expression of several apoptotic related proteins. It was recently shown to directly target Bcl-2 mRNA and upregulate Bcl-2 protein expression. Nevertheless, the possible effect of miR-21 in autophagy has never been addressed. This study investigates the effects of targeting miR-21 with antimiRs on chronic myeloid leukemia cellular autophagy and on associated drug sensitivity. We observed that miR-21 downregulation decreased cellular viability and proliferation, although no changes to the normal cell cycle profile were observed. miR-21 downregulation also caused increased programmed cell death and a decrease in the expression levels of Bcl-2 protein, although PARP cleavage was not affected, indicating that apoptosis was not the relevant mechanism underlying the observed results. Treatment with antimiR-21 caused an increase in the autophagy related proteins Beclin-1, Vps34 and LC3-II. Accordingly, autophagic vacuoles were visualized both by monodansylcadaverine (MDC) and acridine orange (AO) staining and also by transmission electron microscopy (TEM). Additionally, miR-21 downregulation increased K562 and KYO-1 cellular sensitivity to etoposide or doxorubicin. This chemosensitivity was reverted by pre-treating cells with 3-MA, an autophagy inhibitor. Finally, serum starvation (an autophagy inducer) also increased sensitivity to these drugs, confirming that autophagy sensitized these cells to the effect of these drugs. To the best of our knowledge, this is the first description of autophagy induction via miR-21 targeting and its involvement in drug sensitivity.
PMID: 23834154 [PubMed - indexed for MEDLINE]
Predicting treatment outcomes in older patients with acute myelogenous leukemia.
Clin Adv Hematol Oncol. 2013 Oct;11(10):669-71
Authors: Klepin HD
PMID: 24518379 [PubMed - in process]
Bcr-Abl activates AURKA and AURKB in chronic myeloid leukemia cells via AKT signaling.
Int J Cancer. 2014 Mar 1;134(5):1183-94
Authors: Yang J, Ikezoe T, Nishioka C, Udaka K, Yokoyama A
This study explored molecular mechanisms by which Bcr-Abl induced expression of Aurora kinase A and B (AURKA and AURKB) in chronic myeloid leukemia cells. Lentiviral transduction of Bcr-Abl into either Ba/F3 or CD34(+) hematopoietic stem/progenitor cells potently increased levels of AURKA and AURKB in association with phosphorylation of AKT and stimulated their proliferation. Bcr-Abl-mediated expression of AURKA and AURKB were decreased in CD34(+) HSPCs when AKT was inactivated by an shRNA against AKT, suggesting that Bcr-Abl induced expression of AURKA and AURKB via AKT signaling. MLN8237, an inhibitor of AURKA, significantly inhibited the proliferation of freshly isolated CD34(+) CML cells in a dose-dependent manner as measured by colony forming assay. Importantly, inhibition of AURKA in CD34(+) leukemia cells freshly isolated from individuals with blast crisis of CML with Bcr-Abl T315I mutant (n = 2) by MLN8237 significantly impaired the engraftment of these cells in severely immunocompromised mice and decreased the weight of spleens. Taken together, Bcr-Abl induces expression of AURKA and AURKB at least in part via AKT. Inhibition of AURKA could be useful to overcome imatinib-resistance mediated by Bcr-Abl mutants.
PMID: 23934627 [PubMed - indexed for MEDLINE]
Donor selection for killer immunoglobulin-like receptors B haplotype of the centromeric motifs can improve the outcome after HLA-identical sibling hematopoietic stem cell transplantation.
Biol Blood Marrow Transplant. 2014 Jan;20(1):98-105
Authors: Zhou H, Bao X, Wu X, Tang X, Wang M, Wu D, He J
After hematopoietic stem cell transplantation (HSCT), natural killer (NK) cell alloreactivity in HLA cells of recipients is regulated by killer immunoglobulin-like receptors (KIRs) on donor NK cells. The effect of KIRs on HSCT outcomes is controversial, particularly in those undergoing HLA-identical sibling HSCT. In this study, effects of KIR and HLA genotypes on the HSCT outcome were investigated in a 5-year retrospective study comprising 219 patient-donor pairs undergoing HLA-identical sibling HSCT for myeloid and lymphoid malignancies. We found that 39.7% (87 of 219) of these pairs, which were KIR mismatched, had better overall survival (OS) and reduced grade III to IV acute graft-versus-host disease (aGVHD), especially in acute myeloid leukemia (AML) patients. Bx1 donor KIR genotype with haplotype B on a telomeric region was a risk factor for the OS and relapse-free survival (RFS). Donor centromeric (c) and telomeric (t) KIR haplotype analysis showed that donor KIR cB-tA/tB was associated with improved OS and RFS compared with cA-tA or cA-tB. Furthermore, donor KIR B haplotype of the centromeric motifs (Cen-B) was an independent beneficial factor in improving OS and RFS and in protecting from relapse after HSCT. In AML patients, the occurrence of aGVHD was significantly lower in HLA-C1 group compared with that in HLA-C2 group, although such effect was not observed in patients with acute lymphoblastic leukemia or chronic myelogenous leukemia. Our results suggest that KIR could impact outcome and donor KIR haplotype with Cen-B confer significant survival benefits to HLA-identical sibling HSCT.
PMID: 24516895 [PubMed - in process]
Report of patients with chronic myeloid leukemia, from hematology clinic, Ahmedabad, Gujarat 2000-2010 at 1(st) myelostone meeting: Indian evidence of chronic myelogenous leukemia.
Indian J Med Paediatr Oncol. 2013 Jul;34(3):193-5
Authors: Deotare UR, Chudgar U, Bhagat E
The data of 156 patients was presented from Hematology clinic, Ahmedabad. This hematology clinic caters large number of the population from Gujarat as well as from neighboring states such as Rajasthan and Madhya Pradesh. Out of 156 patients, 146 (94%) patients were in chronic phase. Complete hematological response was seen in 90% of patients and overall survival was 82% at 5 years.
PMID: 24516308 [PubMed]
Report of chronic myelogenous leukemia in chronic phase from, Asian Institute of Oncology, Mumbai, 2002-2010.
Indian J Med Paediatr Oncol. 2013 Jul;34(3):168-71
Authors: Bansal S, Advani SH
Chronic myeloid leukemia (CML) has paradigm shift in its treatment modality after the discovery of targeted therapy Imatinib. At our centre we collected data of 100 consecutive patients over a period of 8 years. The interesting finding in our study was difference in the survival of patients presenting in early chronic phase (81%) versus late chronic phase (16%). Also the patients with primary resistance did poorly compared to the patients who developed secondary resistance to Imatinib.
PMID: 24516300 [PubMed]
Donor selection for KIR B haplotype of the centromeric motifs can improve the outcome after HLA-identical sibling hematopoietic stem cell transplantation.
Biol Blood Marrow Transplant. 2013 Oct 25;
Authors: Zhou H, Bao X, Wu X, Tang X, Wang M, Wu D, He J
After hematopoietic stem cell transplantation (HSCT), natural killer (NK) cell alloreactivity in human leukocyte antigen (HLA) cell of recipients is regulated by killer immunoglobulin-like receptors (KIRs) on donor NK cells. The effect of KIRs on HSCT outcomes is controversial, particularly in those undergoing HLA-identical sibling HSCT. In this study, effects of KIR and HLA genotypes on the HSCT outcome were investigated in a 5-year retrospective study comprising 219 patient-donor pairs undergoing HLA-identical sibling HSCT for myeloid and lymphoid malignancies. We found that 39.7% (87/219) of these pairs who were KIR mismatched had better overall survival (OS) and reduced III-IV acute graft-versus-host disease (aGVHD), especially in acute myeloid leukemia (AML) patients. Bx1 donor KIR genotype with haplotype B on a telomeric region was a risk factor for the OS and relapse-free survival (RFS). Donor centromeric (c) and telomeric (t) KIR haplotype analysis showed that donor KIR cB-tA/tB was associated with improved OS and RFS compared with cA-tA or cA-tB. Furthermore, donor KIR B haplotype of the centromeric motifs (Cen-B) was an independent beneficial factor in improving OS and RFS and in protecting from relapse after HSCT. In AML patients, the occurrence of aGVHD was significantly lower in HLA-C1 group compared to that in HLA-C2 group, while such effect was not observed in patients with acute lymphoblastic leukemia or chronic myelogenous leukemia. Our results suggest that KIR could impact outcome and donor KIR haplotype with Cen-B confer significant survival benefits to HLA-identical sibling HSCT.
PMID: 24513672 [PubMed - as supplied by publisher]
Clinical application of catalytically cleavable fluorescence probe technology for multiplexing quantification of BCR-ABL1 fusion transcripts.
Clin Chim Acta. 2013 Oct 25;
Authors: Park KJ, Woo YM, Kim K, Lee ST, Ki CS, Kim HJ, Kim SH, Kim JW
BACKGROUND: Accurate measurement of BCR-ABL1 fusion transcripts is critical for therapeutic stratification in patients with chronic myelogenous leukemia (CML). Previous studies have reported the variable performance of the existing quantitative reverse transcription polymerase chain reaction (RQ-PCR). Here, we developed a one-step multiplex RQ-PCR method based on the catalytically cleavable fluorescence probe technology for quantification of BCR-ABL1 transcripts.
METHODS: Performance was evaluated with respect to the limit of detection (LoD), linearity, precision, and comparison on the VIIA7 Real-Time PCR system. Multiplex RQ-PCR was performed by the one-step and one-well reaction without the hands-on time.
RESULTS: Our assay showed a LoD of 1.5pg with linearity in the range of more than 4 log of dilution. Intraassay, interassay, and total percent CVs at the concentration of 150ng were 12.8%, 22.6%, and 28.0%, respectively. The assay correlated well with Asuragen’s BCR/ABL1 Quant(TM) kit over a 6 log concentration range (r=0.9967).
CONCLUSION: Our assay demonstrated comparable performance characteristics in comparison with previous RQ-PCR based on the TaqMan probe technology. We conclude that our method could be a reliable tool in the clinical setting.
PMID: 24513328 [PubMed - as supplied by publisher]
Ponatinib in Philadelphia chromosome-positive leukemias.
N Engl J Med. 2014 Feb 6;370(6):577
Authors: Quintas-Cardama A
PMID: 24499222 [PubMed - indexed for MEDLINE]
Ponatinib in Philadelphia chromosome-positive leukemias.
N Engl J Med. 2014 Feb 6;370(6):577
Authors: Cortes JE, Talpaz M, Kantarjian H
PMID: 24499221 [PubMed - indexed for MEDLINE]
The genetic basis of myelodysplasia and its clinical relevance.
Blood. 2013 Dec 12;122(25):4021-34
Authors: Cazzola M, Della Porta MG, Malcovati L
Myelodysplasia is a diagnostic feature of myelodysplastic syndromes (MDSs) but is also found in other myeloid neoplasms. Its molecular basis has been recently elucidated by means of massive parallel sequencing studies. About 90% of MDS patients carry ?1 oncogenic mutations, and two thirds of them are found in individuals with a normal karyotype. Driver mutant genes include those of RNA splicing (SF3B1, SRSF2, U2AF1, and ZRSR2), DNA methylation (TET2, DNMT3A, and IDH1/2), chromatin modification (ASXL1 and EZH2), transcription regulation (RUNX1), DNA repair (TP53), signal transduction (CBL, NRAS, and KRAS), and cohesin complex (STAG2). Only 4 to 6 genes are consistently mutated in ?10% MDS patients, whereas a long tail of ?50 genes are mutated less frequently. At presentation, most patients typically have 2 or 3 driver oncogenic mutations and hundreds of background mutations. MDS driver genes are also frequently mutated in other myeloid neoplasms. Reliable genotype/phenotype relationships include the association of the SF3B1 mutation with refractory anemia with ring sideroblasts, TET2/SRSF2 comutation with chronic myelomonocytic leukemia, and activating CSF3R mutation with chronic neutrophilic leukemia. Although both founding and subclonal driver mutations have been shown to have prognostic significance, prospective clinical trials that include the molecular characterization of the patient’s genome are now needed.
PMID: 24136165 [PubMed - indexed for MEDLINE]
Selected parameters of hemostasis in patients with myeloproliferative neoplasms.
Blood Coagul Fibrinolysis. 2014 Feb 6;
Authors: Gadomska G, Ro?? D, Stankowska K, Boinska J, Ruszkowska-Ciastek B, Wieczór R
Hemostatic disorders are a major clinical problem in patients with myeloproliferative neoplasms (MPNs) and they are the second most common cause of death in MPN patients, after infections. The aim of this study was to assess the fibrinolytic potential of the blood of patients with MPNs. The study involved 112 patients with MPNs diagnosed at the Hematology Clinic Dr J. Biziel University Hospital No. 2 in Bydgoszcz, Poland. The study group included 63 patients with essential thrombocythemia, 29 with polycythemia vera, 11 with chronic myelogenous leukemia (CML) and nine with primary myelofibrosis. The control group consisted of 25 healthy volunteers who were age and sex-matched. The following parameters were determined: concentration of tissue plasminogen activator antigen (t-PA:Ag), plasminogen activator inhibitor type 1 antigen concentration (PAI-1:Ag), D-dimer, thrombin-antithrombin complexes, fibrinogen, activated partial thromboplastin time and international normalized ratio. The study showed significantly increased t-PA:Ag, PAI-1:Ag and D-dimer levels in patients with MPNs. Moreover, we found increased concentrations of thrombin-antithrombin complexes and fibrinogen, as well as elevated platelet counts. Detailed analysis revealed that t-PA:Ag concentration was elevated in patients with essential thrombocythemia, CML and polycythemia vera. Concentration of PAI-1:Ag was increased in patients with essential thrombocythemia and polycythemia vera; D-dimer was significantly higher in essential thrombocythemia, polycythemia vera, CML and primary myelofibrosis patients. Increased concentrations of t-PA:Ag and D-dimer indicate secondary activation of the fibrinolytic system in patients with MPNs. Elevated levels of PAI-1 in MPN patients may result from its increased production by elevated number of activated platelets and vascular endothelial damage. PAI-1 by having an inhibitory effect on fibrinolysis manifests its procoagulant activity.
PMID: 24509338 [PubMed - as supplied by publisher]