Chronic Myeloid Leukaemia News Headlines

Promyelocytic blast crisis of chronic myeloid leukemia during imatinib treatment.

Ann Clin Lab Sci. 2008;38(3):283-6

Authors: Chung HJ, Chi HS, Cho YU, Park CJ, Seo EJ, Kim KH, Lee JH

A 32-yr-old man with the chronic phase of chronic myeloid leukemia (CML-CP) was treated with imatinib mesylate for 6 mo. The real-time quantitative reverse transcription PCR ratio for BCR/ABL in blood mRNA (BCR/ABL RT-QPCR) decreased from an initial value of 0.0159 to a low value of 0.0012 after 3 mo, indicating complete hematologic response. During the next 3 mo, the patient progressed to a promyelocytic blast crisis, displaying leukemic cells containing both BCR/ABL and PML/RARalpha chimeric mRNAs. Complete remission was achieved by therapy with all-trans retinoic acid (ATRA) and high-dose imatinib mesylate. Using retrospective PML/RARalpha RT-QPCR with a bone marrow specimen obtained at the initial diagnosis of CML-CP, we quantified the mRNA ratio as 0.000321, suggesting that the clonal evolution of PML/RARalpha translocation occurred early in the CML-CP.

PMID: 18715859 [PubMed - in process]

Advanced Glycation End Products Accumulate in Vascular Smooth Muscle and Modify Vascular but Not Ventricular Properties in Elderly Hypertensive Canines.

Circulation. 2008 Aug 18;

Authors: Shapiro BP, Owan TE, Mohammed SF, Meyer DM, Mills LD, Schalkwijk CG, Redfield MM

BACKGROUND: -Advanced glycation end products (AGEs) are believed to increase left ventricular (LV) and vascular stiffness, in part via cross-linking proteins. We determined whether and where AGEs were increased in elderly hypertensive nondiabetic dogs and whether an AGE cross-link breaker (ALT-711) improved vascular or ventricular function. Methods and Results-Elderly dogs with experimental hypertension (old hypertensives [OH]) were randomized to receive ALT-711 (OH+ALT group; n=11; 1 mg/kg PO) or not (OH group; n=11) for 8 weeks. Conscious blood pressure measurements (weekly), echocardiography (week 8), and anesthetized study (week 8) with LV pressure-volume analysis and aortic pressure-dimension and pressure-flow assessment over a range of preloads and afterloads were performed. In LV and aorta from OH, OH+ALT, and young normal dogs, AGE content (immunohistochemistry and Western analysis for N(epsilon)-(carboxymethyl)lysine [CML]) was assessed. Aortic CML content was markedly increased in OH and OH+ALT dogs compared with young normal dogs. CML was localized to aortic and aortic vasa vasorum smooth muscle but not to collagen or elastin. CML was essentially undetectable in young normal, OH, or OH+ALT myocardium but was visible in large vessels in the LV. ALT-711 therapy was associated with lower blood pressure and pulse pressure, decreased systemic vascular resistance, increased aortic distensibility and arterial compliance, and, notably, significant aortic dilatation. Neither LV systolic nor diastolic function was different in OH+ALT versus OH dogs. Conclusions-In elderly hypertensive canines, AGE accumulation and AGE cross-link breaker effects were confined to the vasculature without evidence of myocardial accumulation or effects. The lack of AGE accumulation in collagen-rich areas suggests that the striking vascular effects may be mediated by mechanisms other than collagen cross-linking.

PMID: 18711013 [PubMed - as supplied by publisher]

Porcine CFSE mixed lymphocyte reaction and PKH-26 cell-mediated lympholysis assays.

Transpl Immunol. 2008 Aug 15;

Authors: Oku M, Okumi M, Sahara H, Hirakata A, Onoe T, Griesemer AD, Yamada K

Mixed lymphocyte reaction (MLR) and cell-mediated lympholysis (CML) are widely used to assess T cell responses. A major limitation of the traditional MLR and CML assays is that they require radioisotope labeling with (3)H for MLR and (51)Cr for CML, thereby limiting their use to laboratories with the capabilities to deal safely with these materials. Recently, flow cytometry with CFSE labeling has been used to detect cell division in rodent and human assays, and flow cytometry with PKH-26 labeling has been used to study cytotoxicity in murine models. Partially inbred miniature swine provide a unique large animal preclinical model for experimental transplantation, helping to bridge the gap between rodent and clinical studies. In this study, we modified the reported CFSE and PKH-26 labeling procedures for use with porcine cells, and established that these radioactive-free MLR and CML assays are comparable to traditional radioactive CML and MLR assays for assessing immunologic responses in miniature swine. To our knowledge, this is the first report that has directly compared the traditional CML/MLR with radiation-free CML/MLR in MHC-defined swine models. OBJECTIVE: The aim of this study is to establish non-radiolabeled CSFE and PKH-26 labeling procedures for flow cytometry based CML/MLR assays that are comparable to radioactive CML/MLR assays in preclinical large animals.

PMID: 18718865 [PubMed - as supplied by publisher]

Targeting cyclooxygenase-2 in hematological malignancies: rationale and promise.

Curr Pharm Des. 2008;14(21):2051-60

Authors: Bernard MP, Bancos S, Sime PJ, Phipps RP

There is much interest in the potential use of Cox-2 selective inhibitors in combination with other cancer therapeutics. Malignancies of hematopoietic and non-hematopoietic origin often have increased expression of cyclooxygenase-2 (Cox-2), a key modulator of inflammation. For example, hematological malignancies such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiple myeloma often highly express Cox-2, which correlates with poor patient prognosis. Expression of Cox-2 enhances survival and proliferation of malignant cells, while negatively influencing anti-tumor immunity. Hematological malignancies expressing elevated levels of Cox-2 potentially avoid immune responses by producing factors that enhance angiogenesis and metastasis. Cellular immune responses regulated by natural killer cells, cytotoxic T lymphocytes, and T regulatory cells are also influenced by Cox-2 expression. Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies.

PMID: 18691115 [PubMed - in process]

Severity of diabetic microvascular complications is associated with a low soluble RAGE level.

Diabetes Metab. 2008 Aug 11;

Authors: Grossin N, Wautier MP, Meas T, Guillausseau PJ, Massin P, Wautier JL

AIMS: The receptor for advanced glycation end-products (RAGE) has been implicated in diabetic microvascular complications, but several lines of evidence suggest that the soluble isoform of RAGE (sRAGE) may protect against AGE-mediated vessel damage. The characterized AGE Nvarepsilon-carboxymethyllysine (CML) is associated with diabetic microvascular complications. In the present study, we measured blood levels of sRAGE and CML-protein in diabetic patients with and without microvascular complications. METHODS: Thirty patients with type-2 diabetes were recruited into the study, comprising 20 who had no microvascular complications, and 10 who had both retinal and renal complications. sRAGE was measured in serum by ELISA, and CML by competitive ELISA. RESULTS: sRAGE blood levels were similar in both the controls and diabetic patients without microvascular complications. In patients with complications, the mean sRAGE blood level was significantly decreased (1068+/-231pg/mL) compared with diabetic patients without complications (P=0.028). CML-protein was increased in all diabetic patients, but to a higher extent in those who had microvascular complications. CONCLUSION: The association of low sRAGE with high CML-protein levels in diabetic patients who developed severe diabetic complications supports the hypothesis that sRAGE protects vessels against AGE-mediated diabetic microvascular damage.

PMID: 18701333 [PubMed - as supplied by publisher]

Proteomic analysis of peanut seed storage proteins and genetic variation in a potential peanut allergen.

Protein Pept Lett. 2008;15(6):567-77

Authors: Guo B, Liang X, Chung SY, Holbrook CC, Maleki SJ

Peanut allergy is one of the most severe food allergies. One effort to alleviate this problem is to identify peanut germplasm with lower levels of allergens which could be used in conventional breeding to produce a less allergenic peanut cultivar. In this study, we identified one peanut line, GT-C9, lacking several seed proteins, which were identified as Ara h 3 isoforms by peptide sequencing and named iso-Ara h 3. Total seed proteins were analyzed by one-dimensional (SDS-PAGE) and two-dimensional gel electrophoreses (2-D PAGE). The total protein extracts were also tested for levels of protein-bound end products or adducts such as advanced glycation end products (AGE) and N-(carboxymethyl) lysine (CML), and IgE binding. Peanut genotypes of GT-C9 and GT-C20 exhibited significantly lower levels of AGE adducts and of IgE binding. This potential peanut allergen iso-Ara h 3 was confirmed by peptide sequences and Western blot analysis using specific anti-Ara h 1, Ara h 2, and Ara h 3 antibodies. A full-length sequence of iso-ara h 3 (GenBank number DQ855115) was obtained. The deduced amino acid sequence iso-Ara h 3 (ABI17154) has the first three of four IgE-binding epitopes of Ara h 3. Anti-Ara h 3 antibodies reacted with two groups of protein peptides, one with strong reactions and another with weak reactions. These peptide spots with weak reaction on 2-D PAGE to anti-Ara h 3 antibodies are subunits or isoallergens of this potential peanut allergen iso-Ara h 3. A recent study suggested that Ara h 3 basic subunits may be more significant allergenicity than the acidic subunits.

PMID: 18680451 [PubMed - in process]

Inhibitors of ABL and the ABL-T315I Mutation.

Curr Top Med Chem. 2008;8(10):905-21

Authors: Noronha G, Cao J, Chow CP, Dneprovskaia E, Fine RM, Hood J, Kang X, Klebansky B, Lohse D, Mak CC, McPherson A, Palanki MS, Pathak VP, Renick J, Soll R, Zeng B

Chronic myelogenous leukemia (CML) is a hematological stem cell disorder caused by increased and unregulated growth of myeloid cells in the bone marrow, and the accumulation of excessive white blood cells. Abelson tyrosine kinase (ABL) is a non-receptor tyrosine kinase involved in cell growth and proliferation and is usually under tight control. However, 95% of CML patients have the ABL gene from chromosome 9 fused with the breakpoint cluster (BCR) gene from chromosome 22, resulting in a short chromosome known as the Philadelphia chromosome. This Philadelphia chromosome is responsible for the production of BCR-ABL, a constitutively active tyrosine kinase that causes uncontrolled cellular proliferation. An ABL inhibitor, imatinib, was approved by the FDA for the treatment of CML, and is currently used as first line therapy. However, a high percentage of clinical relapse has been observed due to long term treatment with imatinib. A majority of these relapsed patients have several point mutations at and around the ATP binding pocket of the ABL kinase domain in BCR-ABL. In order to address the resistance of mutated BCR-ABL to imatinib, 2(nd) generation inhibitors such as dasatinib, and nilotinib were developed. These compounds were approved for the treatment of CML patients who are resistant to imatinib. All of the BCR-ABL mutants are inhibited by the 2(nd) generation inhibitors with the exception of the T315I mutant. Several 3(rd) generation inhibitors such as AP24534, VX-680 (MK-0457), PHA-739358, PPY-A, XL-228, SGX-70393, FTY720 and TG101113 are being developed to target the T315I mutation. The early results from these compounds are encouraging and it is anticipated that physicians will have additional drugs at their disposal for the treatment of patients with the mutated BCR-ABL-T315I. The success of these inhibitors has greater implication not only in CML, but also in other diseases driven by kinases where the mutated gatekeeper residue plays a major role.

PMID: 18673174 [PubMed - in process]

[Imatinib treatment of our chronic myeloid leukemia patients.]

Orv Hetil. 2008 Aug 10;149(32):1509-12

Authors: Egyed M, Kollár B, Rajnics P, Karádi E, Matolcsi A

Chronic myeloid leukemia is a malignant clonal alteration of the pluripotent hemopoietic stem cell. The genetic hallmarks of the disease are the t(9,22) (Philadelphia chromosome), registered by conventional cytogenetics in more than 90% of all chronic myeloid leukemia cases and the active tyrosine kinase protein encoded by bcr-abl fusion gene. The constitutively active tyrosine kinase is currently accepted to be the cause of chronic myeloid leukemia. The introduction of imatinib has considerably changed the treatment of chronic myeloid leukemia. Prior studies demonstrated high rates of cytogenetic responses in all phases of the disease. Methods: The authors evaluated the cytogenetic and molecular responses of 21 chronic phase chronic myeloid leukemia patients who were consecutively admitted to their center. 13 of them were primarily treated with imatinib, and the other 7 were heavily pretreated with interferon alfa, cytarabine, all-trans-retinoic acid. Hydroxiurea pretreatment was routinely introduced in all patients until complete hematologic remission. Peripheral blood sample in every 3 months were collected for quantitative real-time polimerase chain reaction, and bone marrow aspirate in every 6 months for conventional cytogenetics. Results: Hematologic remission could have been achieved with hydroxiurea pretreatment in each patient. Complete cytogenetic remission at the 6th month and major molecular response at the 12th month were observed in each patient. Conclusions: Imatinib treatment caused complete cytogenetic response and major molecular response in each chronic phase chronic myeloid leukaemia patient in our group. Hydroxiurea might have some effect on the rapid and deep cytogenetic and molecular responses, observed in the primary imatinib-treated group.

PMID: 18672441 [PubMed - in process]

Dasatinib inhibits progenitor cell proliferation from polycythaemia vera.

Eur J Clin Invest. 2008 Aug;38(8):578-84

Authors: Wappl M, Jaeger E, Streubel B, Gisslinger H, Schwarzinger I, Valent P, Oehler L

BACKGROUND: A mutation of Janus kinase 2 V617F is present in most patients with polycythaemia vera (PV). However, it is generally believed that JAK2(V617F) is not the sole molecular abnormality in PV. Since dasatinib is currently evaluated in patients with PV, it is of interest to study the effects of dasatinib on the growth of clonal progenitor cells in vitro. DESIGN AND METHODS: Peripheral blood mononuclear cells from patients with PV, chronic myeloid leukaemia (CML) and controls were exposed to dasatinib (0.1 to 500 nm mL(-1)). Colony growth was stimulated by interleukin-3, granulocyte-macrophage colony-stimulating factor and erythropoietin. Endogenous erythroid colony (EEC) growth was investigated without exogenous cytokines. Real-time PCR was performed to assess the percentage of JAK2(V617F) cells. RESULTS: 10 nm of dasatinib suppressed EEC growth from PV by 89% (P = 0.002). This inhibition was dose dependent and occurred at pharmacological concentrations. Erythroid and myeloid colony growth was also significantly suppressed in the presence of exogenous cytokines. When compared to PV the inhibition of stimulated colony growth was significantly less pronounced in controls but tended to be more vigorous in CML. Interestingly, despite the potent inhibition of PV cells real-time PCR revealed that the numbers of JAK2(V617F) transcripts did not decrease upon exposure to dasatinib. CONCLUSION: This study shows a marked inhibition of the proliferative capacity of progenitor cells from PV. Although JAK2(V617F) transcript levels did not decrease upon exposure to dasatinib, the drug might suppress PV progenitors through inhibition of a yet undefined molecular target.

PMID: 18717827 [PubMed - in process]

Different kinetic patterns of BCR-ABL transcript levels in imatinib-treated chronic myeloid leukemia patients after achieving complete cytogenetic response.

Int J Lab Hematol. 2008 Aug;30(4):317-23

Authors: Qin YZ, Liu YR, Zhu HH, Li JL, Ruan GR, Zhang Y, Jiang Q, Jiang H, Li LD, Chang Y, Huang XJ, Chen SS

Bone marrow BCR-ABL transcript levels were monitored serially by real-time quantitative PCR in 46 imatinib-treated chronic myeloid leukemia patients after achieving complete cytogenetic response (CCyR) for a median of 42 months (range: 9-53). Of 41 patients in continuous CCyR, 32 and nine could achieve a >/=3-log (MMoR group) or 2- to 3-log reduction (non-MMoR group), respectively. The MMoR group had a significantly lower recurrence rate of Ph+ metaphase than the non-MMoR group (6/32 vs. 7/9, P = 0.002), which was not significantly different between patients first achieving CCyR within or after 12 months of imatinib treatment (7/27 vs. 6/14, P = 0.086). Five patients suffered cytogenetic or hematological relapse. For all 46 patients, a >2-log reduction but not time when CCyR was first achieved was related to a lower relapse rate (1/42 vs. 4/4, P < 0.001). We concluded that the depth of BCR-ABL reduction after CCyR is more critical than when CCyR is first achieved. The kinetic pattern of BCR-ABL transcript is a good predictor of disease stability.

PMID: 18665830 [PubMed - in process]

Double Philadelphia-chromosome: a resistance factor on the imatinib mesylate therapy for chronic myeloid leukemia.

Int J Lab Hematol. 2008 Aug;30(4):346-8

Authors: Otero L, Ornellas MH, Dobbin J, de Souza Fernandez T

PMID: 18665834 [PubMed - in process]