In vitro Anti-leukaemia Activity of Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs).
Recent Pat Anticancer Drug Discov. 2010 Jan 1;
Authors: Marfe G, Di Stefano C
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by unregulated growth of myeloid leukemia cells in the bone marrow and accumulation of these cells in the blood. CML represents approximately 15-20% of all adult leukemia and the disease development is clearly linked to the constitutively active tyrosine kinase of the chimeric protein BCR-ABL. It is encoded by the Bcr-Abl fusion gene sequence as the result of chromosome 9/22 translocation (Philadelphia chromosome) or other aberrant cytogenetic events. The development of targeted agents that specifically inhibit the tyrosine kinase (TK) activity of BCR-ABL has revolutionized the treatment of CML. Imatinib is now the first-line treatment for chronic phase CML, and several newer tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib have been added to the pharmacologic compendium. Despite the proven efficacy of TKIs to induce hematological and cytogenetic remission, the large majority of patients still have molecularly detectable disease. Therefore, new options are needed to improve therapeutic success in the treatment of leukemia. Pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxides (PBTDs) induced apoptosis in human BCR-ABL expressing leukemia cells. The apoptotic activity was also observed in primary leukemic blasts, obtained from CML patients at onset or from patients in blast crisis and who were imatinib- dasatinib- and nilotinib resistant. These results suggests that these compounds are promising agent for the treatment of leukemia. Due to the fact that the phenomenon of resistance to TKIs remains a major issue in the treatment of patients with CML, the identification of new drugs may be of clinical relevance. This review summarises patents and papers dealing with the present understanding of mechanism of action and the most relevant data concerning TKs inhibition.
PMID: 19663771 [PubMed - as supplied by publisher]
Epigenetic down-regulation of BIM expression is associated with reduced optimal responses to imatinib treatment in chronic myeloid leukaemia.
Eur J Cancer. 2009 Jul;45(10):1877-89
Authors: San José-Eneriz E, Agirre X, Jiménez-Velasco A, Cordeu L, Martín V, Arqueros V, Gárate L, Fresquet V, Cervantes F, Martínez-Climent JA, Heiniger A, Torres A, Prósper F, Roman-Gomez J
BACKGROUND: Expression of the pro-apoptotic BCL-2-interacting mediator (BIM) has recently been implicated in imatinib-induced apoptosis of BCR-ABL1(+) cells. However, the mechanisms involved in the regulation of BIM in CML and its role in the clinical setting have not been established. DESIGN AND METHODS: We analysed the mRNA expression of BIM in 100 newly diagnosed patients with CML in chronic phase by Q-RT-PCR and the protein levels by Western blot analysis. Methylation status was analysed by bisulphite genomic sequencing and MSP. CML cell lines were treated with imatinib and 5-aza-2′-deoxycytidine, and were transfected with two different siRNAs against BIM and cell proliferation and apoptosis were analysed. RESULTS: We demonstrated that down-regulation of BIM expression was present in 36% of the patients and was significantly associated with a lack of optimal response to imatinib as indicated by the decrease in cytogenetic and molecular responses at 6, 12 and 18 months in comparison with patients with normal BIM expression (p<0.05). Expression of BIM was mediated by promoter hypermethylation as demonstrated by restoration of BIM expression after treatment of CML cells with 5-aza-2′-deoxycytidine. Using CML cell lines with low and normal expression of BIM we further demonstrated that the expression of BIM is required for imatinib-induced CML apoptosis. CONCLUSION: Our data indicate that down-regulation of BIM is epigenetically controlled by methylation in a percentage of CML patients and has an unfavourable prognostic impact, and that the combination of imatinib with a de-methylating agent may result in improved responses in patients with decreased expression of BIM.
PMID: 19403302 [PubMed - indexed for MEDLINE]
Extracellular NM23 protein promotes the growth and survival of primary cultured human acute myelogenous leukemia cells.
Cancer Sci. 2009 Jul 8;
Authors: Okabe-Kado J, Kasukabe T, Honma Y, Kobayashi H, Maseki N, Kaneko Y
An elevated serum level of NM23-H1 protein is found in acute myelogenous leukemia (AML), and predicts a poor treatment outcome in AML patients. To investigate the potential pathological link between the elevated serum level of this protein and poor prognosis, we examined the extracellular effects of recombinant NM23-H1 protein on the in vitro growth and survival of primary cultured AML cells at concentrations equivalent to the levels found in the serum of AML patients. Extracellular NM23-H1 protein promoted the in vitro growth and survival of AML cells and this activity was associated with the cytokine production and activation of the MAPK and signal transducers and activators of transcription signaling pathways. Inhibitors specific to MAPK signaling pathways inhibited the growth- and survival-promoting activity of NM23-H1. These findings indicate the novel biological action of extracellular NM23-H1 and its association with poor prognosis, and suggest an important role for extracellular NM23-H1 in the malignant progression of leukemia and a potential therapeutic target for these malignancies.
PMID: 19664043 [PubMed - as supplied by publisher]
Can a high platelet count be responsible for diabetes insipidus in acute myelogenous leukemia with monosomy 7 and inversion 3 (q21q26)?
Int J Hematol. 2009 Aug 12;
Authors: Sonmez M, Erkut N, Tat TS, Celep F, Cobanoglu U, Ersoz HO
PMID: 19669858 [PubMed - as supplied by publisher]
Reactivation of chronic hepatitis B infection related to imatinib mesylate therapy.
Hepatol Int. 2008 Dec;2(4):498-9
Authors: Lakhani S, Davidson L, Priebat DA, Sherker AH
Imatinib (Gleevec, Novartis), an inhibitor of BCR-ABL, platelet-derived growth factor, and KIT receptor tyrosine kinases, is widely used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. We describe a case of activation of chronic hepatitis B infection associated with imatinib therapy.
PMID: 19669326 [PubMed - in process]
Killer immunoglobulin-like receptors (KIR2DL2 and/or KIR2DS2) in presence of their ligand (HLA-C1 group) protect against chronic myeloid leukaemia.
Tissue Antigens. 2009 Jun;73(6):553-60
Authors: Middleton D, Diler AS, Meenagh A, Sleator C, Gourraud PA
We have analysed the frequency of killer immunoglobulin-like receptors (KIR) in cohorts of patients from Turkey with acute lymphocyte leukaemia (n = 52), acute myeloid leukaemia (n = 54) and chronic myeloid leukaemia (CML) (n = 52) and compared the results with 154 controls. We also examined the frequencies of human leucocyte antigen (HLA)-C groups, -Bw4, -Bw6 and where appropriate the combination of the KIR gene and its ligand. We found several statistically significant results between the patients and the controls. We proposed a model in CML of protection via KIR2DL2 and/or KIR2DS2 with the presence of the ligand HLA-C1 group and susceptibility via HLA-Bw4 homozygosity (i.e. absence of HLA-Bw6).
PMID: 19493232 [PubMed - indexed for MEDLINE]
MRSA-pyomyositis in a patient with acute myelogenous leukemia after intensive chemotherapy.
Anticancer Res. 2009 Aug;29(8):3361-4
Authors: Fukushima T, Iwao H, Nakazima A, Miki M, Sakai T, Sawaki T, Tanaka M, Masaki Y, Hirose Y, Umehara H
BACKGROUND: A case of methicillin-resistant Staphylococcus aureus (MRSA)-pyomyositis in association with acute myelogenous leukemia (AML) is reported. MRSA-sepsis developed in a 51-year-old Japanese man with AML, during the neutropenic period after high-dose 1-beta-d-arabinofuranosylcytosine (Ara-C). Although the MRSA-sepsis initially improved with arbekacin sulfate (ABK) administration, a high fever recurred with left thigh pain despite recovery of the neutrophil count after ABK was stopped. A computed tomographic (CT) scan showed a low-density area in the left quadriceps femoris muscle, which led to a diagnosis of pyomyositis. MRSA was cultured from the abscess aspirates. The fever and thigh pain disappeared after administration of ABK and minocycline hydrochloride (MINO), and the abscess completely disappeared with the oral administration of levofloxacin (LVFX) for about 3 months. CONCLUSION: If an immunocompromised patient complains of fever and muscle pain after intensive chemotherapy, MRSA-pyomyositis should be considered.
PMID: 19661356 [PubMed - in process]
Low relapse without excessive transplant-related mortality following myeloablative cord blood transplantation for acute leukemia in complete remission: a matched cohort analysis.
Biol Blood Marrow Transplant. 2009 Sep;15(9):1122-9
Authors: Gutman JA, Leisenring W, Appelbaum FR, Woolfrey AE, Delaney C
Growing evidence supports the efficacy of cord blood transplantation (CBT), and the number of CBTs is increasing. Numerous studies confirm the presence of a graft-versus-leukemia (GVL) effect following CBT, and preliminary data suggests that double-unit CBT may be associated with a decreased risk of relapse. We have observed a low relapse rate following CBT among patients with acute leukemias in morphologic complete remission (CR) at the time of myeloablative (MA) transplant. To further assess this observation, we conducted a matched cohort analysis comparing relapse rates and outcomes for patients receiving CBTs versus patients receiving matched unrelated donor (MURD) and mismatched unrelated donor (MMURD) transplants at our center. Thirty-one consecutive CBT patients (aged 0.6-42 years, median 22 years), transplanted between April 2006 and June 2008, were compared to matched subjects selected on the basis of disease type and remission number, cytogenetic risk status, minimal residual disease status (MRD), time from diagnosis to first relapse (for patients beyond CR1), use of imatinib for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) patients, age, and date of transplant. With a median follow-up among surviving CBT patients of 21.1 months (range: 6.6-32.6 months), there has been 1 relapse among cord patients versus 8 relapses among MURD patients (P=.018) and 7 relapses among MMURD patients (P=.019). Treatment-related mortality (TRM) between cohorts is comparable. Although we have observed a high incidence of acute graft-versus-host disease (aGVHD) following CBT, the incidence of National Institutes of Health (NIH) consensus criteria chronic GVHD (cGVHD) has been low. These data support increased investigation of the use of CBT.
PMID: 19660726 [PubMed - in process]
Lymphocyte recovery is a major determinant of outcome after matched unrelated myeloablative transplantation for myelogenous malignancies.
Biol Blood Marrow Transplant. 2009 Sep;15(9):1108-15
Authors: Le Blanc K, Barrett AJ, Schaffer M, Hägglund H, Ljungman P, Ringdén O, Remberger M
A higher absolute lymphocyte count 1 month (LC30) after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with better outcome in patients transplanted from a matched sibling. We studied 102 SCT patients with unrelated donor and matched unrelated donors and the relationship between LC30 and outcome in patients with myelogenous leukemia. Conditioning was myeloablative using cyclophosphamide (Cy) with busulfan (Bu; n=61) or total body irradiation (TBI; n=41). LC30 was low (<0.2×10(9)/L) in 18 patients, intermediate (0.2-1.0×10(9)L) in 67, and high (>1.0×10(9)/L) in 17 patients. In multivariate analysis, independent factors associated with high relapse-free survival (RFS) were high LC30, high CD34 cell-dose, and absence of acute graft-versus-host disease (aGVHD) grades II-IV. When analyzed as a continuous variable in multivariate analysis, a higher LC30 was associated with a lower transplant-related mortality (TRM; relative hazard [RH]=0.87, P < .05), higher relapse-free survival (RH=3.42, P=.036), and improved survival (RH=4.53, P=.016, excluding GVHD). In patients with high, intermediate, and low LC30, overall survival (OS) was 91% versus 60%, versus 36% (P=.02 and .001, respectively). This significant relationship was maintained in patients who did not develop GVHD by day 30. Significant risk factors to develop low LC30 was chronic myelogenous leukemia (CML; hazard ratio [HR] 0.73, P=.001), prophylaxis with granulocyte colony-stimulating factor (G-CSF; HR 0.81, P=.02) and aGVHD (HR 0.84, P=.05). These results indicate that LC30 is an independent prognostic factor for transplant outcome in matched unrelated SCT for myelogenous malignancies.
PMID: 19660724 [PubMed - in process]
Moderate renal function impairment does not affect outcomes of reduced-intensity conditioning with fludarabine and melphalan for allogeneic hematopoietic stem cell transplantation.
Biol Blood Marrow Transplant. 2009 Sep;15(9):1094-9
Authors: de Souza JA, Saliba RM, Patah P, Rondon G, Ribeiro R, de Padua Silva L, Qazilbash MH, Hosing C, Popat U, Efebera Y, Champlin RE, de Lima M
Nonrelapse mortality (NRM) after reduced-intensity allogeneic transplants is likely to be influenced by abnormalities in renal function. We studied 141 patients diagnosed with acute myelogenous leukemia (AML) (n = 131) or high-risk myelodysplastic syndrome (MDS) (n = 10) who underwent allogeneic transplantation with fludarabine (Flu)/melphalan (Mel)-based regimens and hypothesized that moderate to mild renal function impairment increases NRM in this setting. Flu dose consisted of 25-30 mg/m(2) for 4 days and Mel dose was 100-180 mg/m(2). Donors were HLA-compatible siblings (n = 69) and matched unrelated donors (n = 72). Disease status at transplantation was complete remission (n = 56, 40%) or active disease (n = 85, 60%). The influence of the estimated glomerular filtration rate (GFR) measured before transplantation on outcomes was analyzed. GFR was estimated by both the Cockcroft-Gault (CG) and the modified diet in renal disease (MDRD) equations, using the creatinine value obtained prior to starting chemotherapy. Evaluated outcomes were overall survival (OS), NRM, and treatment-related mortality (TRM) at day 100 and 1-year posttransplantation. Median age was 55 years (range: 21-74 years); 59% of the patients were male. Estimated GFR by CG was > or =90 for 45 (32%), 60-89 for 78 (55%), and <60 for 18 (13%) patients. When estimated by MDRD, GFR was > or =90 for 65 (46%), 60-89 from 66 (47%), and <60 for 10 (7%) patients. The majority of patients by both estimations had a GFR between 60 and 89 (n = 78 by CG and n = 66 by MDRD) with no difference in the evaluated outcomes between this group and the subgroup of patients with a GFR <60 (P > .05). There were no differences in OS and NRM at day 100 and 1-year posttransplantation in the 3 groups by any GFR estimation method. In conclusion, a mild to moderate decrease in GFR was not associated with an increase in NRM.
PMID: 19660722 [PubMed - in process]
The Notch ligands Jagged2, Delta1, and Delta4 induce differentiation and expansion of functional human NK cells from CD34(+) cord blood hematopoietic progenitor cells.
Biol Blood Marrow Transplant. 2009 Sep;15(9):1026-37
Authors: Beck RC, Padival M, Yeh D, Ralston J, Cooke KR, Lowe JB
Notch receptor signaling is required for T cell development, but its role in natural killer (NK) cell development is poorly understood. We compared the ability of the 5 mammalian Notch ligands (Jagged1, Jagged2, Delta1, Delta3, or Delta4) to induce NK cell development from human hematopoietic progenitor cells (HPCs). CD34(+) HPCs were cultured with OP9 stromal cell lines transduced with 1 of the Notch ligands or with OP9 stromal cells alone, in the presence of IL-7, Flt3L, and IL-15. Differentiation and expansion of CD56(+)CD3(-) cells were greatly accelerated in the presence of Jagged2, Delta-1, or Delta-4, versus culture in the absence of ligand or in the presence of Jagged1 or Delta3. At 4 weeks, cultures containing Jagged2, Delta1, or Delta4 contained 80% to 90% NK cells, with the remaining cells being CD33(+) myelogenous cells. Notch-induced NK (N-NK) cells resembled CD56(bright) NK cells in that they were CD16(-), CD94(-), CD117(+), and killer immunoglobulin-like receptors (KIR(-)). They also expressed NKp30, NKp44, NKp46, 2B4, and DNAM-1, with partial expression of NKG2D. The N-NK cells displayed cytotoxic activity against the K562 and RPMI-8226 cell lines, at levels similar to activated peripheral blood (PB) NK cells, although killing of Daudi cells was not present. N-NK cells were also capable of interferon (IFN)-gamma secretion. Thus, Notch ligands have differential ability to induce and expand immature, but functional, NK cells from CD34(+) HPCs. The use of Notch ligands to generate functional NK cells in vitro may be significant for cellular therapy purposes.
PMID: 19660715 [PubMed - in process]
A Multinational Study of Health State Preference Values Associated with Chronic Myelogenous Leukemia.
Value Health. 2009 Jul 29;
Authors: Szabo SM, Levy AR, Davis C, Holyoake TL, Cortes J
Objectives: Chronic myelogenous leukemia (CML) is a progressive, largely fatal cancer. Emerging treatments may prolong life; however, these result in additional monetary costs. Accurate estimation of their economic impact requires reliable estimates on preferences for health states. The purpose was to estimate preference weights from the general population in four developed countries for standardized health states experienced by persons with CML. Methods: Time trade-off preferences with a 10-year time horizon were elicited for CML-related health states using an interviewer-administered survey from convenience samples in Canada (n = 103), the United States (n = 74), the UK (n = 97), and Australia (n = 79). Standardized descriptions of seven CML-related health states (characterizing chronic, accelerated and blast phases, each with responding and nonresponding state, and adverse events of treatment) were derived in consultation with oncologists. Generalized linear models were used to estimate whether utilities, adjusted for age and sex, differed by country. Results: The mean age of the sample (n = 357) was 45 years and 46% were male. Mean unadjusted preference values of CML-related health states ranged from 0.84 for “Chronic phase responding to treatment” to 0.21 for “Blast phase, not responding to treatment.” For each phase, preferences were lower for the nonresponding state. After adjustment for age and sex, considerable variability was observed in mean preference values between countries. Conclusion: These data quantify the deteriorating impact of CML disease progression and the impact of nonresponse to treatment. The study results add to evidence from other disease areas that systematic differences exist in preference values between countries.
PMID: 19659707 [PubMed - as supplied by publisher]
Sunitinib, an orally available receptor tyrosine kinase inhibitor, induces monocytic differentiation of acute myelogenous leukemia cells that is enhanced by 1,25-dihydroxyvitamin D(3).
Leukemia. 2009 Aug 6;
Authors: Nishioka C, Ikezoe T, Yang J, Yokoyama A
PMID: 19657366 [PubMed - as supplied by publisher]
Plerixafor inhibits chemotaxis toward SDF-1 and CXCR4-mediated stroma contact in a dose-dependent manner resulting in increased susceptibility of BCR-ABL(+) cell to Imatinib and Nilotinib.
Leuk Lymphoma. 2009 Aug 3;:1-11
Authors: Dillmann F, Veldwijk MR, Laufs S, Sperandio M, Calandra G, Wenz F, Zeller WJ, Fruehauf S
Despite Imatinib’s remarkable success in chronic myelogenous leukemia treatment, monotherapy frequently causes resistance, underlining the rationale for combination chemotherapy. A potential approach would be interrupting the SDF-1/CXCR4 axis using the selective CXCR4 antagonist Plerixafor (previously AMD3100), as this axis has been reported to provide survival-enhancing effects to myeloid progenitor cells. By efficient CXCR4 blocking in the CXCR4(+)/BCR-ABL(+) cell line BV-173, plerixafor (1-100 muM) significantly inhibits SDF-1alpha-mediated chemotaxis and cell migration toward the murine stroma cell line FBMD-1. Furthermore, plerixafor also significantly (10-100 muM) increased the detachment rate of SDF-1-mediated/VCAM-1-associated cell adherence under shear stress. Using a stroma-dependent coculture assay, plerixafor sensitized BCR-ABL(+) cells toward tyrosine kinase inhibitor therapy. Because the level of cell killing nearly reached that of samples cultured without stroma, a cell-cell interaction disruption seems to improve the efficacy of BCR-ABL-targeting drugs. In addition, we could show that exposure of BCR-ABL(+) cells to Imatinib or Nilotinib induced an increase in surface CXCR4 expression. Our data suggest that for BCR-ABL(+) leukemia, the selective blocking of the SDF-1/CXCR4 axis by plerixafor is a potential mechanism to overcome the protective effect of the bone marrow environment, thereby increasing the therapeutic potency of anti-BCR-ABL drugs and the therapeutic window.
PMID: 19657955 [PubMed - as supplied by publisher]
Influence of lactate dehydrogenase and cyclosporine A level on the incidence of acute graft-versus-host disease after allogeneic stem cell transplantation.
J Korean Med Sci. 2009 Aug;24(4):555-60
Authors: Song MK, Chung JS, Seol YM, Kwon BR, Shin HJ, Choi YJ, Cho GJ
Previous reports have suggested that a high serum cyclosporine A (CsA) level could result in a lower incidence of acute-graft-versus-host disease (aGVHD). An elevated serum lactate dehydrogenase (LDH) level has been reported to be an adverse predictor of outcome in stem cell transplantation (SCT) for acute myeloid leukemia. In this study, we retrospectively analyzed the records of 24 patients who received allogeneic SCT from an HLA-matched sibling donor for acute and chronic myelogenous leukemia. Univariate analysis showed that two factors (the serum CsA level at the third week after SCT and the LDH level at the third week after SCT) were significantly associated with the incidence of aGVHD among several variables (age, sex, stem cell source, cell dose, C-reactive protein, absolute lymphocyte count, conditioning regimens, and time to engraftment). A higher serum level of CsA and lower serum LDH level at the third week after SCT were associated with a lower incidence of aGVHD (P=0.015, 0.030). In multivariate analysis, the serum CsA level (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.022-0.652, P=0.0014) and serum LDH level (HR, 6.59; 95% CI, 1.197-36.316, P=0.030) at the third week after SCT were found to be independent factors that were significantly associated with the development of aGVHD. We conclude that a high CsA level and low LDH level might predict a low cumulative incidence of aGVHD after allogeneic transplantation from a matched sibling donor.
PMID: 19654932 [PubMed - in process]
Cytoplasmic mutated nucleophosmin (NPM1) in blast crisis of chronic myeloid leukaemia.
Leukemia. 2009 Jul;23(7):1370-1
Authors: Piccaluga PP, Sabattini E, Bacci F, Agostinelli C, Righi S, Salmi F, Testoni N, Paolini S, Castagnetti F, Martinelli G, Falini B, Pileri SA
PMID: 19421226 [PubMed - indexed for MEDLINE]
Prevalence of gallstones in patients with chronic myelocytic leukemia.
Med Princ Pract. 2009;18(3):175-9
Authors: Ates F, Erkurt MA, Karincaoglu M, Aladag M, Aydogdu I
OBJECTIVE: The aim of the present case-control study was to determine whether or not the prevalence of gallbladder stones (GBS) was increased in patients with chronic myelocytic leukemia (CML) and to investigate clinical and laboratory characteristics of CML patients with GBS. SUBJECTS AND METHODS: This study included 56 patients with CML and 55 sex- and age-matched healthy controls. All participants underwent abdominal ultrasonography and the main clinical and laboratory characteristics were recorded. RESULTS: Gallbladder stones were detected in 13 (23.6%) patients with CML and in 3 (5.4%) control individuals (p < 0.05). The mean follow-up period of CML patients after diagnosis was 54.6 months, range 3-120 months. Hemoglobin levels were higher in the control group than in CML patients. However, total bilirubin, unconjugated bilirubin, lactate dehydrogenase levels, leukocyte and thrombocyte counts, frequency of splenomegaly and hepatomegaly were higher in the CML than in the control group (p < 0.05). Other clinical and laboratory values were not significantly different between the groups. CML patients with and without GBS were also compared for clinical and laboratory values. Age and follow-up period of CML patients after diagnosis were higher in the CML patients with GBS (p < 0.05). CONCLUSIONS: Higher prevalence of GBS in CML patients than in healthy controls was detected. We suggest that CML may increase the frequency of GBS, apart from other well-known risk factors. This risk is probably related to increased unconjugated bilirubin, which determines hemolysis, older age and long follow-up period of CML patients after diagnosis.
PMID: 19349718 [PubMed - indexed for MEDLINE]
Extracellular NM23-H1 protein inhibits the survival of primary cultured normal human peripheral blood mononuclear cells and activates the cytokine production.
Int J Hematol. 2009 Aug 5;
Authors: Okabe-Kado J, Kasukabe T, Honma Y, Kobayashi H, Maseki N, Kaneko Y
An elevated serum level of NM23-H1 protein is found in acute myelogenous leukemia (AML) and predicts a poor treatment outcome for AML patients. To investigate the potential pathological link between the elevated serum level of this protein and poor prognosis, we examined the extracellular effects of recombinant NM23-H1 protein on the in vitro survival of primary cultured normal peripheral blood mononuclear cells (PBMNC) at concentrations equivalent to the levels found in the serum of AML patients. Extracellular NM23-H1 protein inhibited the in vitro survival of PBMNC and promoted the production of various cytokines, such as GM-CSF and IL-1beta, which in fact promoted the growth of primary cultured AML cells. These findings indicate a novel biological action of extracellular NM23-H1 and its association with poor prognosis of patients with elevated serum levels of NM23-H1 protein. These results suggest an important role of extracellular NM23-H1 in the malignant progression of leukemia and a potential therapeutic target for these malignancies.
PMID: 19655221 [PubMed - as supplied by publisher]
The constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway commonly occurs in cancers and is a crucial event in tumorigenesis. Chronic myelogenous leukemia (CML) is characterized by a reciprocal chromosomal translocation (9;22) that generates the Bcr-Abl fusion gene. The PI3K/Akt pathway is activated by Bcr-Abl chimera protein and mediates the leukemogenesis in CML. However, the mechanism by which Bcr-Abl activates the PI3K/Akt pathway is not completely understood. In the present study, we found that pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1 and PHLPP2) were depleted in CML cells. We investigated the interaction between PHLPPs and Bcr-Abl in CML cell lines and Bcr-Abl+ progenitor cells from CML patients. The Abl kinase inhi…
A higher absolute lymphocyte count 1 month (LC30) after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with better outcome in patients transplanted from a matched sibling. We studied 102 SCT patients with unrelated donor and matched unrelated donors and the relationship between LC30 and outcome in patients with myelogenous leukemia. Conditioning was myeloablative using cyclophosphamide (Cy) with busulfan (Bu; n=61) or total body irradiation (TBI; n=41). LC30 was low (1.0×109/L) in 17 patients. In multivariate analysis, independent factors associated with high relapse-free survival (RFS) were high LC30, high CD34 cell-dose, and absence of acute graft-versus-host disease (aGVHD) grades II-IV. When analyzed as a continuous variable in multivariate analysis, a higher …