Notch activation inhibits AML growth and survival: a potential therapeutic approach.
J Exp Med. 2013 Jan 28;
Authors: Kannan S, Sutphin RM, Hall MG, Golfman LS, Fang W, Nolo RM, Akers LJ, Hammitt RA, McMurray JS, Kornblau SM, Melnick AM, Figueroa ME, Zweidler-McKay PA
Although aberrant Notch activation contributes to leukemogenesis in T cells, its role in acute myelogenous leukemia (AML) remains unclear. Here, we report that human AML samples have robust expression of Notch receptors; however, Notch receptor activation and expression of downstream Notch targets are remarkably low, suggesting that Notch is present but not constitutively activated in human AML. The functional role of these Notch receptors in AML is not known. Induced activation through any of the Notch receptors (Notch1-4), or through the Notch target Hairy/Enhancer of Split 1 (HES1), consistently leads to AML growth arrest and caspase-dependent apoptosis, which are associated with B cell lymphoma 2 (BCL2) loss and enhanced p53/p21 expression. These effects were dependent on the HES1 repressor domain and were rescued through reexpression of BCL2. Importantly, activated Notch1, Notch2, and HES1 all led to inhibited AML growth in vivo, and Notch inhibition via dnMAML enhanced proliferation in vivo, thus revealing the physiological inhibition of AML growth in vivo in response to Notch signaling. As a novel therapeutic approach, we used a Notch agonist peptide that led to significant apoptosis in AML patient samples. In conclusion, we report consistent Notch-mediated growth arrest and apoptosis in human AML, and propose the development of Notch agonists as a potential therapeutic approach in AML.
PMID: 23359069 [PubMed - as supplied by publisher]
Gene mutations and molecularly targeted therapies in acute myeloid leukemia.
Am J Blood Res. 2013;3(1):29-51
Authors: Hatzimichael E, Georgiou G, Benetatos L, Briasoulis E
Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period of time. However, over the last 30 years fine-tuning of therapeutics have increased the rates of remission and cure. Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3, JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in clinical development. For loss-of-function gene mutations, which are mostly biomarkers of favorable prognosis, combined therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products, proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their biological functions and clinical significance and present small molecule compounds in clinical development, which are expected to have a role in treating AML subtypes with characteristic molecular alterations.
PMID: 23358589 [PubMed]
[Myeloproliferative neoplasms related glomerulopathy.]
Rev Med Interne. 2013 Jan 25;
Authors: Paule R, Ponsoye M, Gueutin V, Deray G, Izzedine H
Myeloproliferative neoplasms (MPNs, formerly called chronic myeloproliferative disorders) are clonal hematopoietic stem cell disorders characterized by the expansion of one or more of the myeloid lineages, including polymorphonuclear, erythroid, megakaryocytic, and mastocytic. The major complications of MPN are transformation into acute myeloid leukemia (occurring particularly in chronic myelogenous leukemia) and thrombotic and hemorrhagic events (most commonly observed in polycythemia vera and essential thrombocythemia). Renal involvement by MPN is infrequent. MPN-related glomerulopathy enlarges the spectrum of glomerular diseases associated with haematological neoplasms. MPN-related glomerulopathy is an under recognized late renal complication of MPN with poor prognosis. It is characterized clinically by heavy proteinuria and renal insufficiency. The histologic features of MPN-related glomerulopathy include variable degree of mesangial sclerosis and hypercellularity, segmental sclerosis, features of chronic thrombotic microangiopathy, and intracapillary hematopoietic cell infiltration. PDGF and TGF? likely have a crucial role in the pathogenesis of MPN-related glomerulopathy. Furthermore, aggregation of circulating hematopoietic cells within glomerular capillaries could potentially result in endothelial injury and morphologic changes resembling chronic thrombotic microangiopathy. Greater awareness of this entity is needed to define diagnosis and possible therapies.
PMID: 23357690 [PubMed - as supplied by publisher]
Immune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes).
Biochem Soc Trans. 2013 Feb 1;41(1):245-51
Authors: Whiteside TL
Body fluids of cancer patients contain TEXs (tumour-derived exosomes). Tumours release large quantities of TEXs, and the protein content of exosome or MV (microvesicle) fractions isolated from patients’ sera is high. TEXs down-regulate functions of immune cells, thus promoting tumour progression. We isolated TEXs from tumour cell supernatants and sera of patients with solid tumours or AML (acute myelogenous leukaemia). The molecular profile of TEXs was distinct from that of circulating exosomes derived from normal cells. TEXs were co-incubated with activated T-cells, conventional CD4+CD25neg T-cells or CD56+CD16+ NK (natural killer) cells respectively. TEXs down-regulated CD3? and JAK3 (Janus kinase 3) expression in primary activated T-cells and mediated Fas/FasL (Fas ligand)-driven apoptosis of CD8+ T-cells. TEXs promoted CD4+CD25neg T-cell proliferation and their conversion into CD4+CD25hiFOXP3+ (FOXP3 is forkhead box P3) Treg cells (regulatory T-cells), which also expressed IL-10 (interleukin 10), TGF?1 (transforming growth factor ?1), CTLA-4 (cytotoxic T-lymphocyte antigen 4), GrB (granzyme B)/perforin and effectively mediated suppression. Neutralizing antibodies specific for TGF?1 and/or IL-10 inhibited the ability of TEXs to expand Treg cells. TEXs obtained at diagnosis from AML patients’ sera were positive for blast-associated markers CD33, CD34, CD117 and TGF?1, and they decreased cytotoxic activity of NK cells isolated from NC (normal control) donors, induced Smad phosphorylation and down-regulated NKG2D receptor expression. Correlations between the TEX molecular profile or TEX protein levels and clinical data in cancer patients suggest that TEX-mediated effects on immune cells are prognostically important. In contrast with exosomes released by normal cells, TEXs have immunosuppressive properties and are involved in regulating peripheral tolerance in patients with cancer.
PMID: 23356291 [PubMed - in process]
Sudden blast crisis in a chronic myeloid leukemia patient during imatinib therapy.
Rom J Intern Med. 2012 Jul-Sep;50(3):241-4
Authors: Voican I, Vl?d?reanu AM, Bumbea H, Begu M
Imatinib mesilate (IM) is the first line therapy for chronic myeloid leukemia (CML) patients in chronic phase. Although it offers a complete cytogenetic response (CCyR) in a majority of patients, there still are some rare cases in which a sudden blast crisis (SBC) evolves. The mechanism of this unexpected event is not yet completely understood. We present the case of a female patient who developed a SBC while being under IM therapy. We do not know for sure which is the role of IM in this event, but current available data suggest that this drug may have a permissive effect on the evolution of some aggressive subclones in the context of restored normal cell population.
PMID: 23330292 [PubMed - indexed for MEDLINE]
Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
Ann Oncol. 2012 Oct;23 Suppl 7:vii72-7
Authors: Baccarani M, Pileri S, Steegmann JL, Muller M, Soverini S, Dreyling M, ESMO Guidelines Working Group
PMID: 22997458 [PubMed - indexed for MEDLINE]
Imaging proliferation in human leukemia-tumor bearing mice with (18)F-FLT: Comparison with (18)F-FDG PET.
Hell J Nucl Med. 2012 Sep-Dec;15(3):206-9
Authors: Lu L, Jiang L, Guan H, Gao Y, Lu H
Leukemia threatens human life due to its uncontrolled proliferative malignancy. 3′-deoxy-3′-(18)F-fluorothymidine ((18)F-FLT) has been suggested as a new positron emission tomography (PET) tracer for imaging tumor proliferation. The aim of the study was to investigate the usefulness of (18)F-FLT PET for imaging human leukemia-tumor bearing mice, compared with fluorine-18-fluorodesoxyglucose ((18)F-FDG PET). In vitro the experiments of (18)F-FLT and (18)F-FDG uptake were performed in K562 cell lines at various time points and radioactive tracer uptake was measured in a gamma counter. (18)F-FLT and (18)F-FDG PET imaging were performed both in the same mouse when eight tumor-bearing mice models of human chronic myeloid leukemia were established successfully by injecting K562 cells. Regions of interest were drawn over the tumor, the crossed normal tissue was regarded as background and the ratio of tumor to non-tumor counts (T/NT) in tissues was calculated. A higher uptake of (18)F-FLT (15min, 5.73±0.05%; 30min, 5.90±0.06%; 60min, 6.16±0.19%; 120min, 6.32±0.08%) than that of (18)F-FDG (15min, 1.05±0.10%; 30min, 1.11±0.14%; 60min, 1.14±0.37%; 120 min, 1.36±0.25%) was observed in K562 cells in the tracer uptake experiment. Ratios of T/NT of (18)F-FLT PET (0.5h, 5.39±0.42; 1h, 4.88±0.43; 2h, 3.81±0.38) were higher than those of (18)F-FDG PET/CT (0.5h, 0.34±0.12; 1h, 0.21±0.06; 2h, 0.13±0.05) after injection. Both uptake and T/NT differences of (18)F-FLT versus (18)F-FDG were significant (P>0.05). In conclusion, (18)F-FLT and (18)F-FDG quantitative and semi-quantitative uptake measurements resulting from cell lines and PET imaging respectively suggested a promising potential of (18)F-FLT for metabolic imaging of human chronic myeloid leukemia.
PMID: 23106052 [PubMed - indexed for MEDLINE]
Design, synthesis, and biological evaluation of 3-(1H-1,2,3-triazol-1-yl)benzamide derivatives as Potent Pan Bcr-Abl inhibitors including the threonine(315)?isoleucine(315) mutant.
J Med Chem. 2012 Nov 26;55(22):10033-46
Authors: Li Y, Shen M, Zhang Z, Luo J, Pan X, Lu X, Long H, Wen D, Zhang F, Leng F, Li Y, Tu Z, Ren X, Ding K
A series of 3-(1H-1,2,3-triazol-1-yl)benzamide derivatives were designed and synthesized as new Bcr-Abl inhibitors by using combinational strategies of bioisosteric replacement, scaffold hopping, and conformational constraint. The compounds displayed significant inhibition against a broad spectrum of Bcr-Abl mutants including the gatekeeper T315I and p-loop mutations, which are associated with disease progression in CML. The most potent compounds 6q and 6qo strongly inhibited the kinase activities of Bcr-Abl(WT) and Bcr-Abl(T315I) with IC(50) values of 0.60, 0.36 and 1.12, 0.98 nM, respectively. They also potently suppressed the proliferation of K562, KU812 human CML cells, and a panel of murine Ba/F3 cells ectopically expressing either Bcr-Abl(WT) or any of a panel of other Bcr-Abl mutants that have been shown to contribute to clinical acquired resistance, including Bcr-Abl(T315I), with IC(50) values in low nanomolar ranges. These compounds may serve as lead compounds for further development of new Bcr-Abl inhibitors capable of overcoming clinical acquired resistance against imatinib.
PMID: 23088644 [PubMed - indexed for MEDLINE]
Hematocolpos as a complication of chronic graft-versus-host disease.
Taiwan J Obstet Gynecol. 2012 Jun;51(2):292-3
Authors: Kim TH, Lee HH, Chung SH
PMID: 22795113 [PubMed - indexed for MEDLINE]
Evaluation of residual CD34(+) Ph(+) progenitor cells in chronic myeloid leukemia patients who have complete cytogenetic response during first-line nilotinib therapy.
Cancer. 2012 Nov 1;118(21):5265-9
Authors: Defina M, Ippoliti M, Gozzetti A, Abruzzese E, Castagnetti F, Crupi R, Tiribelli M, Breccia M, Salvucci M, Aprile L, Baratè C, Gozzini A, Rosti G, Lauria F, Bocchia M
BACKGROUND: Compared with imatinib, nilotinib is a potent breakpoint cluster region/v-abl Abelson murine leukemia viral oncogene (bcr-abl) kinase inhibitor, and it induces higher rate and rapid complete cytogenetic response (CCyR), yet no clinical data are available regarding its efficacy against chronic myeloid leukemia (CML) stem cells. Earlier studies demonstrated that clusters of differentiation 34-positive, Philadelphia chromosome-positive (CD34(+) Ph(+) ) cells are detectable in about 45% of patients with CML, despite being on long-term imatinib therapy and having achieved sustained CCyR.
METHODS: CD34(+) cells from bone marrow of de novo CML patients in the chronic phase (n = 24) treated with nilotinib (median duration of therapy, 22 months) were isolated and scored for BCR-ABL by fluorescent in situ hybridization (FISH) analysis. Similar analysis was also performed in 5 de novo CML chronic phase patients who achieved CCyR within 3 months of nilotinib therapy.
RESULTS: FISH evaluation of a median of 100 CD34(+) nuclei per patient revealed that only 1 of 20 (5%) evaluable patients showed residual Ph(+) progenitor cells. In this patient, just 1 of 140 (0.7%) CD34(+) interphase nuclei was found to be positive for BCR-ABL. Surprisingly, no CD34(+) Ph(+) cells were found even in those 5 patients evaluated after 3 months of nilotinib treatment.
CONCLUSIONS: This study assessed for the first time the persistence of CD34(+) Ph(+) cells during nilotinib first-line treatment. Preliminary results showed that in patients in CCyR, even after short-term nilotinib therapy, residual leukemic progenitors are very rarely detected compared with imatinib-treated CCyR patients. It is yet to be determined if these findings will have an impact in the path to a cure of CML with tyrosine kinase inhibitors.
PMID: 22517301 [PubMed - indexed for MEDLINE]
Reverse phase protein array profiling reveals distinct proteomic signatures associated with chronic myeloid leukemia progression and with chronic phase in the CD34-positive compartment.
Cancer. 2012 Nov 1;118(21):5283-92
Authors: Quintás-Cardama A, Qiu YH, Post SM, Zhang Y, Creighton CJ, Cortes J, Kornblau SM
BACKGROUND: Chronic myeloid leukemia (CML) is a clonal stem cell malignancy whose pathogenesis is driven by constitutive activation of the breakpoint cluster region-v-abl Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) kinase. Although BCR-ABL1 activation is present in all patients with CML, patients can present in 3 different phases characterized by an increasingly worse prognosis and diminished responsiveness to tyrosine kinase inhibitors: chronic phase, accelerated phase, or blastic phase. The biologic basis for progression from chronic phase to blastic phase and for regulating the homeostasis of tyrosine kinase inhibitor-resistant CML stem cells is not entirely understood.
METHODS: To shed some light into these aspects of CML biology, the authors used reverse phase protein arrays probed with 112 individual monoclonal antibodies to compare protein expression patterns in 40 samples of leukemia-enriched fractions from patients with CML (25 in chronic phase, 5 in accelerated phase, and 10 in phase).
RESULTS: An analysis of variance (significance cutoff, P < .01) unveiled a set of proteins that were overexpressed in blastic phase, including heat-shock protein 90 (hsp90); retinoblastoma (Rb); apoptosis-inducing factor (AIF); serine/threonine-protein phosphatase 2A (PP2A); B-cell leukemia 2 (Bcl-2); X-linked inhibitor of apoptosis protein (Xiap); human homolog of Drosophila Mad (mothers against decapentaplegic) and related Caenorhabditis elegans gene Sma, family member 1 (Smad1); single-stranded DNA binding protein 2 alpha (SSBP2?); poly(adenosine diphosphate-ribose) polymerase (PARP); GRB2-associated binding protein 2 (Gab2); and tripartite motif containing 24 (Trim24). It is noteworthy that several of these proteins also were overexpressed in the CD34-positive compartment, which putatively contains the CML stem cell population.
CONCLUSIONS: The results from this study indicated that reverse phase protein array analysis can unveil differentially expressed proteins in advanced phase CML that can be exploited therapeutically with targeted approaches.
PMID: 22517119 [PubMed - indexed for MEDLINE]
Tyrosine kinase inhibitors for elderly chronic myeloid leukemia patients: a systematic review of efficacy and safety data.
Crit Rev Oncol Hematol. 2012 Oct;84(1):93-100
Authors: Breccia M, Tiribelli M, Alimena G
The impact of age as a poor prognostic factor in chronic myeloid leukemia (CML) has been well described. In the interferon era, elderly patients diagnosed as having chronic phase chronic myeloid leukemia (CP-CML) had shorter survival compared to younger patients. With the advent of target therapy with imatinib, several reports described improved responses in elderly late CP-CML patients treated with imatinib after IFN failure, with similar overall survival compared to younger population. Imatinib in newly diagnosed older patients showed similar rate of cytogenetic and molecular responses compared to younger patients. Few data are available relating elderly CML patients subset treated with second-generation TKIs after resistance/intolerance to imatinib: both nilotinib and dasatinib have demonstrated efficacy and limited toxicity profile as in younger patients. The aim of this review is, through the revision of published data, to highlight the fact that elderly CML patients can benefit from target therapy with limited adverse events.
PMID: 22280914 [PubMed - indexed for MEDLINE]
STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis.
Oncogene. 2012 Oct 4;31(40):4384-96
Authors: Sekine Y, Ikeda O, Mizushima A, Ueno Y, Muromoto R, Yoshimura A, Kanakura Y, Oritani K, Matsuda T
In chronic myeloid leukemia (CML), the BCR-ABL fusion oncoprotein activates multiple pathways involved in cell survival, growth promotion and disease progression. In this report, we show that the signal-transducing adaptor protein-2 (STAP-2) is involved in BCR-ABL activity. We demonstrate that STAP-2 bound to BCR-ABL, and BCR and ABL proteins, depending on the STAP-2 Src homology 2-like domain. BCR-ABL phosphorylates STAP-2 Tyr250 and the phosphorylated STAP-2 in turn upregulated BCR-ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK (extracellular-signal-regulated kinase), STAT5 (signal transducer and activator of transcription 5), BCL-xL (B-cell lymphoma-extra large) and BCL-2(B-cell lymphoma 2). In addition, STAP-2 interacts with BCR-ABL to alter chemokine receptor expression leading to downregulation of CXCR4 and upregulation of CCR7. The interaction between STAP-2 and BCR-ABL plays a crucial role in conferring a growth advantage and resistance to imatinib, a BCR-ABL inhibitor, as well as tumor progression. Notably, mice injected with BCR-ABL/STAP-2-expressing Ba/F3 cells developed lymph node enlargement and hepatosplenomegaly. Moreover, suppression of STAP-2 in K562 CML cells resulted in no tumor formation in mice. Our results demonstrate a critical contribution of STAP-2 in BCR-ABL activity, and suggest that STAP-2 might be an important candidate for drug development for patients with CML. Furthermore, the expression of STAP-2 provides useful information for estimating the characteristics of individual CML clones.
PMID: 22231445 [PubMed - indexed for MEDLINE]
Pharmaceutical approval update.
P T. 2012 Nov;37(11):620-49
Authors: Goldenberg MM
Bosutinib (Bosulif) tablets for chronic myelogenous leukemia; linaclotide (Linzess) for irritable bowel syndrome/constipation and chronic idiopathic constipation; and regorefenib (Stivarga) tablets for metastatic colorectal cancer.
PMID: 23204815 [PubMed - in process]
It’s About Time: Lessons for Solid Tumors from Chronic Myelogenous Leukemia Therapy.
Mol Cancer Ther. 2012 Nov 30;
Authors: Westin JR, Kurzrock R
The use of imatinib in chronic myelogenous leukemia (CML) transformed the disease, rapidly changing the median survival from 4 years to at least 20 years. In this review, we outline the causes of this revolution, including the identification of a critical driving molecular aberration, BCR-ABL, and the development of a potent and specific inhibitor, imatinib. Equally important was the timing of the targeted therapy, specifically its administration to patients with newly diagnosed disease. In solid tumors, targeted therapies are often both developed and used in metastatic malignancies after conventional approaches have failed. We postulate that this strategy is similar to using imatinib in blast-crisis CML, in which response rates are less than 15%, all patients relapse, and median survival remains only about 1 year. We hypothesize that the imatinib-led revolution in CML, including the critically important factor of timing, may be applicable to other cancers as well. Therefore, it will be important to use promising targeted therapies in the earliest phases of biomarker-defined solid tumors, before metastatic progression, to determine if outcomes can be significantly improved and, thus, establish if the success of imatinib in CML is an anomaly or a paradigm. Mol Cancer Ther; 11(12); 1-7. ©2012 AACR.
PMID: 23204432 [PubMed - as supplied by publisher]
Induction of Apoptosis, G0/G1 Phase Arrest and Microtubule Disassembly in K562 Leukemia Cells by Mere15, a Novel Polypeptide from Meretrix meretrix Linnaeus.
Mar Drugs. 2012;10(11):2596-607
Authors: Liu M, Zhao X, Zhao J, Xiao L, Liu H, Wang C, Cheng L, Wu N, Lin X
Mere15 is a novel polypeptide from Meretrix meretrix Linnaeus with cytotoxicity in solid cancer cells. In this study, we investigated its activity on human K562 chronic myelogenous leukemia cells. Mere15 inhibited the growth of K562 cells with IC(50) values of 38.2 μg/mL. Mere15 also caused concentration dependent induction of apoptosis, with overproduction of reactive oxygen species and loss of mitochondrial membrane potential. Moreover, Mere15 arrested cell cycle progression at G(0)/G(1) phase of K562 cells in a concentration dependent manner. In addition, Mere15 caused the disassembly of the microtubule cytoskeleton in K562 cells and inhibited the polymerization of tubulin in a cell free system via interaction with tubulin. We concluded that Mere15 was cytotoxic to K562 leukemia cells and the cytotoxicity was related to the apoptosis induction, cell cycle arrest and microtubule disassembly. These results implied that Merer15 was a broad spectrum anticancer polypeptide, not only cytotoxic to various solid cancer cells but also to the chronic myelogenous leukemia cells. Mere15 may have therapeutic potential for the treatment of leukemia.
PMID: 23203280 [PubMed - in process]
Can we improve outcomes in patients with acute myelogenous leukemia? Incorporating HDAC inhibitors into front-line therapy.
Best Pract Res Clin Haematol. 2012 Dec;25(4):427-35
Authors: Garcia-Manero G
There is a need for improvements on the results of current therapies for patients with acute myelogenous leukemia (AML). A number of strategies are being used to achieve this goal. Here we present data that indicate that the addition of a histone deacetylase (HDAC) inhibitor, such as vorinostat, to idarubicin and cytarabine results in a very high response rate and can be safely administered to patients with leukemia. These results form the bases of the next SWOG front-line trial in AML. Here, we present the rationale for such combination and the studies that led to the support of this concept including both in vitro models and initial phase 1 trials.
PMID: 23200539 [PubMed - in process]
Cytomegalovirus infection and ganciclovir resistance caused by UL97 mutations in pediatric transplant recipients.
Transpl Infect Dis. 2012 Jun 22;
Authors: Kim YJ, Boeckh M, Cook L, Stempel H, Jerome KR, Boucek R, Burroughs L, Englund JA
BACKGROUND: Cytomegalovirus (CMV) infection may cause serious disease after hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT), but few reports describe ganciclovir (GCV) resistance in pediatric patients. OBJECTIVES: This study was performed to describe the clinical impact of CMV infection with UL97 mutation in pediatric transplant recipients. METHODS: Quantitative surveillance data for CMV infection in pediatric patients between October 2001 and February 2007 at the University of Washington were analyzed. Testing for UL97 mutation was performed in selected patients with prolonged CMV viremia despite therapy. Data associated with the detection of UL97 mutations were reviewed. RESULTS: CMV was detected in 89 pediatric transplant recipients. Among these, 39 had undergone HCT and 50 SOT (12 heart, 22 kidney, 15 liver, and 1 bilateral lung transplants). CMV with at least one UL97 sequence variation was detected in 5 patients: 4 HCT recipients (4/39, 10%) and 1 heart transplant recipient (1/50, 2%). All 5 pediatric patients were CMV seropositive before transplantation. Underlying conditions included chronic myelogenous leukemia, primary immunodeficiency disorders, and hypoplastic left heart syndrome. One known GCV drug-resistant mutation was detected in 2 HCT recipients (A594V). Three strain variants with mutations considered to have no significant impact on UL97 function (H469Y, N510S, and D605E) were detected. Two of these 5 patients died, 1 because of uncontrolled CMV infection and 1 with other complications. CONCLUSIONS: UL97 drug-resistant mutations occur in pediatric transplant recipients with CMV viremia and can cause serious disease. Screening for mutations conferring resistance to CMV antivirals should be considered for patients with persistent viremia during therapy and the sequences of UL97 mutations evaluated.
PMID: 23198963 [PubMed - as supplied by publisher]
[Acute myelogenous leukemia and chronic myelogenous leukemia in children].
Nihon Rinsho. 2012 Apr;70 Suppl 2:676-80
Authors: Adachi S
PMID: 23134027 [PubMed - in process]
ETV6-NTRK3 as a therapeutic target of small molecule inhibitor PKC412.
Biochem Biophys Res Commun. 2012 Nov 3;
Authors: Chi HT, Ly BT, Kano Y, Tojo A, Watanabe T, Sato Y
The ETV6-NTRK3 (EN) fusion gene which encodes a chimeric tyrosine kinase was first identified by cloning of the t(12;15)(p13;q25) translocation in congenital fibrosarcoma (CFS). Since then, EN has been also found in congenital mesoblastic nephroma (CMN), secretory breast carcinoma (SBC) and acute myelogenous leukemia (AML). Using IMS-M2 and M0-91 cell lines harboring the EN fusion gene, and Ba/F3 cells stably transfected with EN, we demonstrated that PKC412, also known as midostaurin, is an inhibitor of EN. Inhibition of EN activity by PKC412 suppressed the activity of it downstream molecules leading to inhibition of cell proliferation and induction of apoptosis. Our data for the first time suggested that PKC412 could serve as therapeutic drug for treatment of patients with this fusion.
PMID: 23131561 [PubMed - as supplied by publisher]