Biomedical subjects

Z Estrov

Publications and source records attributed to Z Estrov.

At least 19 recordsLinked to original sources

PubMed2006

The JAK-STAT pathway: a therapeutic target in hematological malignancies.

The development and function of hematopoietic cells depends on complex signaling pathways that are mediated by numerous cytokines and their receptors. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is prominent both in normal hematopoiesis and in hematological malignancies. STATs are phosphorylated on tyrosine residues via JAK kinases and on serine residues by a variety of serine/threonine kinases. STATs then dimerize, translocate to the nucleus and bind DNA, initiating the transcription of target genes. STAT proteins mediate cell growth, differentiation, apoptosis, transformation, and other fundamental cell functions. Recently, mutations in the JAK2 gene driving the proliferation of the neoplastic clone have been identified in myeloproliferative disorders. In addition constitutive activation of the JAK-STAT pathway has been reported in various types of leukemias such as acute myelogenous leukemia, T-LGL leukemia, and multiple myeloma. This review describes the pathophysiological role of this pathway in hematological malignancies and the potential benefits of JAK-STAT inhibition.

Animals↗

PubMed2005

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells.

Multiple myeloma (MM) accounts for 1 % of all cancer deaths. Although treated aggressively, almost all myelomas eventually recur and become resistant to treatment. Atiprimod (2-(3-Diethylaminopropyl)-8,8-dipropyl-2-azaspiro[4,5] decane dimaleate) has exerted anti-inflammatory activities and inhibited oeteoclast-induced bone resorption in animal models and been well tolerated in patients with rheumatoid arthritis in phase I clinical trials. Therefore, we investigated its activity in MM cells and its mechanism of action. We found that Atiprimod inhibited proliferation of the myeloma cell lines U266-B1, OCI-MY5, MM-1, and MM-1R in a time- and dose-dependent manner. Atiprimod blocked U266-B1 myeloma cells in the G(0)/G(1) phase, preventing cell cycle progression. Furthermore, Atiprimod inhibited signal transducer and activator of transcription (STAT) 3 activation, blocking the signalling pathway of interleukin-6, which contributes to myeloma cell proliferation and survival, and downregulated the antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1. Incubation of U266-B1 myeloma cells with Atiprimod induced apoptosis through the activation of caspase 3 and subsequent cleavage of the DNA repair enzyme poly(adenosine diphosphate-ribose) polymerase. Finally, Atiprimod suppressed myeloma colony-forming cell proliferation in fresh marrow cells from five patients with newly diagnosed MM in a dose-dependent fashion. These data suggest that Atiprimod has a role in future therapies for MM.

Apoptosis↗

PubMed2005

Umbilical cord blood-derived cells for tissue repair.

Hematopoietic tissue-derived cells, including stem cells, have been shown to generate solid organ tissue-specific cells. Besides bone marrow and peripheral blood, umbilical cord blood (UCB) has the advantage of being an easily accessible stem cell source provided as a banked cell product. Using the xenogeneic human into NOD/SCID mouse stem cell transplant model preliminary data suggest UCB-derived tissue-specific cells generated in liver, pancreas, CNS and endothelium. In a clinical sex-mismatched UCB transplant setting Y-positive, UCB-derived gastrointestinal epithelial cells and CNS-specific cells have been identified in female patients. The potential therapeutic use of UCB cells for tissue repair is, however, limited by a low total stem cell number available and by HLA-disparity.

Animals↗

PubMed2004

Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias.

The phosphatidylinositol 3-kinase (PI3K)/AKT protein kinase pathway is involved in cell growth, proliferation, and apoptosis. The functional activation of PI3K/AKT provides survival signals and blockade of this pathway may facilitate cell death. Downstream targets of PI3K-AKT include the proapoptotic protein BAD, caspase-9, NF-kappaB, and Forkhead. We have previously reported that BAD is constitutively phosphorylated in primary acute myeloid leukemia (AML) cells, a post-transcriptional modification, which inactivates its proapoptotic function. In this study, we tested the hypothesis that the inhibition of PI3K by LY294002 results in the dephosphorylation of AKT and BAD, and thus promote leukemia cell apoptosis. We investigated the effects of LY294002 in megakaryocytic leukemia-derived MO7E cells, primary AML and normal bone marrow progenitor cells. In MO7E cells, LY294002 reduced AKT kinase activity, induced dephosphorylation of AKT and BAD, and increased apoptosis. Concomitant inhibition of mitogen-activated protein kinase signaling or combination with all-trans retinoic acid further enhanced apoptosis of leukemic cells. In primary AML samples, clonogenic cell growth was significantly reduced. Normal hematopoietic progenitors were less affected, suggesting preferential targeting of leukemia cells. In conclusion, the data suggest that the inhibition of the PI3K/AKT signaling pathway restores apoptosis in AML and may be explored as a novel target for molecular therapeutics in AML.

Apoptosis↗

PubMed2004

Circulating stem cells and tissue repair.

Stem cells are defined as cells that have clonogenic, self-renewing capacities and the capability to differentiate into multiple cell lineages. Whereas embryonic stem cells are derived from mammalian embryos in the blastocyst stage and can generate terminally differentiated cells of all 3 embryonic germ layers, adult human stem cells are capable of maintaining, generating, and replacing terminally differentiated cells within their own specific tissue as a consequence of physiologic cell turnover or tissue injury. The traditional idea of organ-restricted stem-cell differentiation is now being challenged by the suggestion that adult stem cells retain developmental plasticity. Preclinical and clinical studies described in this review provide evidence that within the blood circulate not only progenitor cells that differentiate into hematopoietic cells, but also stem/progenitor cells which can participate in the homeostasis, repair and replacement of solid organ tissues. In addition to the occurrence of cell fusion, there are 4 suggested mechanisms of adult stem cell differentiation into solid organ cells. Preclinical data support these models particularly that of transdifferentiation as the most likely model, allowing stem/progenitor cells to differentiate across lineage, tissue, and germ layer boundaries. There is increasing evidence that we can manipulate in vivo circulating adult stem cells to repair or regenerate solid organ tissue, which offers potential clinical benefit in the treatment of many hereditary and acquired diseases.

Animals↗

PubMed2003

Adult stem cells and tissue repair.

Recently, adult stem cells originating from bone marrow or peripheral blood have been suggested to contribute to repair and genesis of cells specific for liver, cardiac and skeletal muscle, gut, and brain tissue. The mechanism involved has been termed transdifferentiation, although other explanations including cell fusion have been postulated. Using adult stem cells to generate or repair solid organ tissue obviates the immunologic, ethical, and teratogenic issues that accompany embryonic stem cells.

Adult↗

PubMed2003

Autocrine lymphotoxin production in Epstein-Barr virus-immortalized B cells: induction via NF-kappaB activation mediated by EBV-derived latent membrane protein 1.

Epstein-Barr virus (EBV)-immortalized lymphoblastoid cells express high levels of lymphotoxin and use this molecule as an autocrine growth factor. We hypothesized that the EBV-derived latent membrane protein 1 (LMP1) mediates lymphotoxin production by inducing NF-kappaB binding to the lymphotoxin promoter. We assessed lymphotoxin production, LMP1 expression, and NF-kappaB activation in Z-43 (EBV-positive lymphoblastoid cells), Daudi (EBV-positive Burkitt's cells), and 3A4 (EBV-negative Burkitt's cells containing a stably transfected tetracycline-inducible LMP1 construct). Z-43 cells expressed high levels of LMP1 (immunoblot) and lymphotoxin (ELISA); the EBV-positive Burkitt's lymphoma line Daudi expressed neither LMP1 nor lymphotoxin. Similarly, induction of LMP1 in the 3A4 cells (exposed to tetracycline) was accompanied by a 13-fold increase in lymphotoxin levels (ELISA) as compared to uninduced (LMP1-negative) cells. EMSAs demonstrated high levels of NF-kappaB activation in Z-43 and tetracycline-induced 3A4 cells, but much lower levels in the uninduced 3A4 cells. Exposure of these cells to Bay 11-7082 (an inhibitor of IkappaB phosphorylation and, therefore, NF-kappaB activation) abrogated NF-kappaB binding and lymphotoxin production in a dose-dependent manner in both Z-43 and 3A4 cells. Therefore, in our model system, autocrine lymphotoxin production is largely driven by NF-kappaB activation, which is in turn mediated by EBV-derived LMP1 signaling.

Animals↗

PubMed2001

Chronic myelogenous leukemia blast cell proliferation is inhibited by peptides that disrupt Grb2-SoS complexes.

Chronic myelogenous leukemia (CML) is commonly characterized by the presence of the p210(Bcr-Abl) oncoprotein. Many downstream effectors of Bcr-Abl have been described, including activation of the Grb2-SoS-Ras-MAP kinase (Erk) pathway. The precise contributions of these signal-transduction proteins in CML blast cells in human patients are not yet well defined. To gain further insight into the importance of Grb2 for CML, peptides that disrupt Grb2-SoS complexes were tested. These high-affinity Grb2-binding peptides (HAGBPs) can autonomously shuttle into cells and function by binding to the N-terminal SH3 domain of Grb2. The HAGBPs were analyzed for their effects on Bcr-Abl-expressing cell lines and freshly isolated CML blast cells from patients. They induced a dramatic decrease in the proliferation of CML cell lines. This was not observed with point-mutated control peptides with abolished Grb2SH3(N) binding. As expected, Grb2-SoS complexes were greatly diminished in the HAGBP-treated cells, and MAP kinase activity was significantly reduced as determined by an activation-specific phospho-MAPK antibody. Furthermore, cell fractions that are enriched for blast cells from CML patients with active disease were also incubated with the Grb2 blocker peptides. The HAGBPs led to a significant proliferation reduction of these cells in the majority of the isolates, but not in all patients' cells. These results show that, in addition to the direct targeting of Bcr-Abl, selective inhibition of Grb2 protein complexes may be a therapeutic option for a significant number of CML patients.

3T3 Cells↗

PubMed2001

Expression of apoptosis proteins in chronic myelogenous leukemia: associations and significance.

BACKGROUND: The mechanisms favoring the growth advantage of Philadelphia chromosome positive cells over normal cells in chronic myelogenous leukemia (CML) are not fully elucidated but could be due partly to altered apoptosis and longer survival of CML clones. Also, little is known about the biologic characteristics of disease progression in CML. Bcl-2 expression has been demonstrated to exert an antiapoptotic effect resulting in increased cell survival. Other proteins such as Bax and Bad are proapoptotic proteins. Fas, a cell surface protein, can be triggered by an appropriate death-promoting ligand (FasL) to activate downstream caspases pivotal in initiation of programmed cell death. Although the mechanisms underlying cellular proliferative and apoptotic pathways are complex, with involvement of multiple interlocking proteins, the relative expression of pro- and antiapoptotic proteins may have an influence on disease progression. This study aimed to determine whether the changes in the cellular expression of Bcl-2, Bax, and Fas correlate with caspase-3 activity and disease progression in CML, or with response to interferon (IFN)-alpha therapy and prognosis in early chronic phase CML. METHODS: Bcl-2, Bax, and Fas expression were measured on whole cell lysates from bone marrow mononuclear cell fractions by Western blot analysis and quantitative radioimmunoassay. Caspase-3 activity was determined using the DEVD system. Specimens from 203 patients with CML were examined. These included 130 patients in early chronic phase disease (ECP; diagnosis to therapy, < or =12 months), 33 patients in late chronic phase (diagnosis to therapy, > 12 months), 27 patients in accelerated phase, and 13 patients in blastic phase. Correlations between apoptosis proteins and CML phases, risk groups in ECP, and response to IFN-alpha therapy and survival in ECP were investigated by standard statistical methods, and positive findings were assessed by multivariate analysis. RESULTS: Levels of Bcl-2, Fas, Bax, and caspase-3 activity did not correlate with disease progression. Among patients in ECP, higher Fas levels correlated with poorer risk groups (P = 0.05) and higher caspase-3 activity correlated with better risk groups (P = 0.048). With IFN-alpha therapy, major cytogenetic responses were noted in 30% of patients with high Fas and 53% with low Fas (P = 0.016) and failure to achieve a complete hematologic response (CHR) in 25% versus 2% (P = 0.0001). Survival was shorter with high Fas levels (5-year rates, 71% vs. 52%; P = 0.002), and the independent poor prognostic significance of high Fas levels was confirmed by multivariate analysis (P = 0.014). Response to IFN-alpha therapy and survival were not significantly different by different levels of Bcl-2, Bax, or caspase-3 activity. CONCLUSIONS: High Fas levels were associated with intrinsically worse disease at diagnosis, whereas high caspase-3 activity was associated with good risk disease. In ECP CML, high Fas levels were associated with significantly worse response to IFN-alpha therapy and with significantly worse survival. The influence of these cellular proteins and caspase-3 activity on apoptosis in CML is complex and merits further investigation.

Adolescent↗

PubMed2001

Expression of a truncated first exon BCR sequence in chronic myelogenous leukemia cells blocks cell growth and induces cell death.

We have shown that a deletion mutant form of Bcr [Bcr(64-413)] is a strong inhibitor of the tyrosine kinase of Bcr-Abl in vitro and also inhibits its oncogenic growth effects (Liu et al., Cancer Res., 56: 5120-5124, 1996). To determine the effects of this Bcr-Abl kinase inhibitor on chronic myelogenous leukemia (CML) cells, we cloned BCR(64-413) into a recombinant, replication-defective adenovirus to express useful quantities of Bcr(64-413) in a wide variety of cells in culture. Infection of Cos1 cells with plaque-purified virus at a multiplicity of infection of 20-40 induced high expression of Bcr(64-413) as detected by Western blotting. Infection of hematopoietic cells at modest multiplicities of infection (20-40) required special conditions involving shifting cycling cells to a nongrowing condition involving serum starvation and cell crowding. Under these conditions, both Bcr-Abl-positive and -negative hematopoietic cells can be efficiently infected by adenovirus, as demonstrated by 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside staining of cells infected by beta-galactosidase (beta-GAL) adenovirus. We found that expression of Bcr(64-413) in Bcr-Abl-positive K562 and BV-173 cells, but not Bcr-Abl-negative SMS-SB cells, increased cell-cell clumping and inhibited cell growth. In contrast to the effects of the Bcr(64-413) adenovirus, the beta-GAL adenovirus, despite infecting both types of cells, did not block growth or increase cell-cell clumping of Bcr-Abl-positive and -negative hematopoietic cells. Expression of Bcr(64-413) protein in primary cultures of cells from CML patients with active disease interfered with cell growth, induced apoptosis (as measured by annexin staining), and increased cell-cell clumping, whereas the beta-GAL adenovirus and mock-infected cells lacked these effects. In contrast, normal marrow cells did not exhibit these effects on infection with Bcr(64-413) adenovirus. We conclude from these findings that Bcr(64-413) interferes with the oncogenic effects of Bcr-Abl and therefore has the potential for use in therapy of CML.

Adenoviridae↗

PubMed2001

Antinuclear autoantibodies as potential antineoplastic agents.

The immune system confines neoplasia at various stages of tumor development. Whereas the role of cellular immunity has been investigated widely and utilized in the clinic, the importance of humoral immunity in this process has begun to emerge only in recent years. Circulating antinuclear autoantibodies (ANAs) typically found in autoimmune conditions, have also been detected in cancer patients and in healthy elderly individuals. The pathogenic role of ANAs in autoimmunity is well studied; however, little research has been carried out to elucidate the functions of ANAs in cancer patients. Experimental data favoring the antitumor activity of ANAs might support the clinical testing of monoclonal ANAs as a cancer therapy, if confirmed by further experiments.

Aging↗

PubMed2001

Comparison of outcome in acute myelogenous leukemia patients with translocation (8;21) found by standard cytogenetic analysis and patients with AML1/ETO fusion transcript found only by PCR testing.

Patients with normal-karyotype acute myelogenous leukemia (NKAML) may have undetected genetic abnormalities that could affect prognosis. Screening for known AML-specific genetic abnormalities using the reverse transcription polymerase chain reaction (RT-PCR) may help in arriving at a more definitive prognosis. To test this hypothesis, 104 patients without translocation (8;21) and inversion(16), as shown by standard cytogenetic (SC) analysis, were screened for these two genetic abnormalities using RT-PCR. Western blot analysis for the AML1/ETO fusion protein and fluorescent in situ hybridization (FISH) analysis for t(8;21) were performed in patients for whom we had samples. The characteristics and outcome after high-dose cytarabine containing treatments in five patients with t(8;21) shown by RT-PCR alone were then compared to 21 patients with t(8;21) detected using SC analysis. Eight of the 104 patients had masked t(8;21) and none had masked inv(16), as shown by RT-PCR. Five of 54 patients with NKAML had a detectable AML1/ETO fusion RNA transcript. Western blot analysis showed the AML1/ETO fusion protein in four of the seven patients for whom we had samples among the eight with masked t(8;21) shown by RT-PCR. All patients with t(8;21) shown by RT-PCR had negative FISH results. Ninety percent (n=19) of the patients with t(8;21) shown by SC analysis and 40% (n= 2) of the patients with t(8;21) shown by RT-PCR alone achieved a complete remission (P value 0.03). These data suggest that the outcome of NKAML patients with t(8;21) shown by RT-PCR is not equivalent to patients with t(8;21) by SC studies.

Adult↗

PubMed2001

Plasma hepatocyte growth factor is a prognostic factor in patients with acute myeloid leukemia but not in patients with myelodysplastic syndrome.

Hepatocyte growth factor (HGF) is a potent angiogenic factor. The aim of our study was to evaluate plasma HGF levels and their prognostic significance in patients with newly diagnosed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The sandwich enzyme immunoassay technique was used to quantify HGF in stored samples obtained before treatment from patients with AML (59 patients) and MDS (42 patients) treated at The University of Texas MD Anderson Cancer Center. HGF levels were significantly higher in patients with AML or MDS than in healthy individuals (P < 0.0001). Higher HGF levels in both AML and MDS correlated significantly with white blood cell (P = 0.000001 for both groups) and monocyte counts (P = 0.0004 and 0.003, respectively), and with poor performance status (P = 0.03 and 0.001, respectively). Using Cox proportional hazard model and HGF levels as a continuous variable, plasma levels of HGF correlated with shorter survival of AML (P = 0.001), but not MDS (P = 0.34) patients. No significant correlation was observed between HGF levels and complete remission rate or duration. In the multivariate analysis HGF retained its significance as prognostic factor in AML (P = 0.02), along with age (P = 0.0005).

Acute Disease↗

PubMed2001

Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia.

The mitogen-activated protein kinase (MAPK) pathway regulates growth and survival of many cell types, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. In this study we demonstrate that small-molecule MEK inhibitors (PD98059 and PD184352) profoundly impair cell growth and survival of acute myeloid leukemia (AML) cell lines and primary samples with constitutive MAPK activation. These agents abrogate the clonogenicity of leukemic cells but have minimal effects on normal hematopoietic progenitors. MEK blockade also results in sensitization to spontaneous and drug-induced apoptosis. At a molecular level, these effects correlate with modulation of the expression of cyclin-dependent kinase inhibitors (p27(Kip1) and p21(Waf1/CIP1)) and antiapoptotic proteins of the inhibitor of apoptosis proteins (IAP) and Bcl-2 families. Interruption of constitutive MEK/MAPK signaling therefore represents a promising therapeutic strategy in AML.

Apoptosis↗

PubMed2001

The clinical significance of caspase regulation in acute leukemia.

Disruptions of pathways of programmed cell death, or apoptosis, are increasingly found in malignant cells of both solid and hematologic neoplasms. Caspases belong to a family of cysteine proteases and have emerged as central regulators of the apoptotic cascade. Despite many and diverse signals that can trigger apoptosis, the execution of apoptosis appears to be uniformly mediated through activation of caspase enzymes. Inapproriate expression of caspases or malfunctions in their regulation through other pathways may also be an important step in the pathogenesis of acute leukemias. Recent studies have shown that overexpression of the inactive forms of caspases CPP32 (caspase 3) and ICH-1 (caspase 2) is frequently observed in the blasts of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Many other enzymes involved in apoptosis are expressed at high levels in patients with acute leukemia. Whether this signals the capacity of leukemic cells to rapid induction of apoptosis with fast reduction of the burden of disease and favorable clinical outcome, or accumulation of inactive substrates that cannot be activated by lack of cellular mechanisms to do so, requires further investigation. With the identification of many other regulators of apoptotic activity in the leukemic cells, new targets for future therapy may be identified and many new insights can be gained in understanding the biological behavior of response and resistance to therapy as well as control and relapse from minimal residual disease.

Acute Disease↗

PubMed2001

High levels of vascular endothelial growth factor receptor-2 correlate with shortened survival in chronic lymphocytic leukemia.

Vascular endothelial growth factor receptor-2 (VEGFR-2), also termed KDR, is a high-affinity vascular endothelial growth factor (VEGF) receptor. VEGFR-2 plays a role in de novo blood vessel formation and hematopoietic cell development. Recently, we found that chronic lymphocytic leukemia (CLL) cells express high levels of VEGF. Therefore, we sought to investigate the role of VEGFR-2 in CLL. Using Western blot analysis, we first determined that VEGFR-2 is present in peripheral blood CLL cells. We then quantified the cellular levels of VEGFR-2 protein using a solid-phase radioimmunoanalysis in peripheral blood cells from 216 patients with CLL. As control, we used peripheral blood mononuclear cells (PBMNCs) from 31 hematologically normal individuals. The median of VEGFR-2 levels detected in the control samples was assigned a value of 1.0, and VEGFR-2 protein levels were normalized to the control median value. The median level of VEGFR-2 in CLL cells was 1.57. Patients with VEGFR-2 levels higher than 1.57 had elevated lymphocyte counts, severe anemia, elevated beta(2)-microglobulin and advanced-stage disease. Elevated VEGFR-2 levels were also associated with statistically significantly shorter survival (35.4 versus 60.1 months; P < 0.01). Our data indicate that cellular VEGFR-2 levels may serve as a prognostic factor in CLL. Further studies should investigate the biological implications of these findings and the effect of the interaction between VEGF and VEGFR-2 on CLL cell proliferation.

Anemia↗

PubMed2000

The prognostic significance of p16(INK4a)/p14(ARF) locus deletion and MDM-2 protein expression in adult acute myelogenous leukemia.

BACKGROUND: The p16(INK4a) locus encodes two distinct proteins, p16(INK4a) and p14(ARF). Although p16(INK4a) and p15(INK4b) are involved in the phosphorylation of the retinoblastoma (Rb) protein, p14(ARF) interacts with the MDM-2 oncoprotein antagonizing its function as a suppressor of p53. The role of deletions of p16(INK4a)/p14(ARF) and p15(INK4b) and expressions of MDM-2 in myeloid leukemias and its influence on prognosis remain unclear. METHODS: The authors analyzed deletions of p16(INK4)/p14(ARF) and p15(INK4b) in 74 adults with acute myeloid leukemia (AML) by Southern blotting. Western blotting was used to determine Rb protein phosphorylation in patients with deletions of p16(INK4)/p14(ARF) and p15(INK4b). Then, they analyzed the levels of MDM-2 protein expression and correlated it with prognosis in an expanded population of 79 adults with AML by immunoblot analysis and solid-phase radioimmunoassay. RESULTS: Deletions of p16(INK4a)/p14(ARF) and/or p15(INK4b) occurred in 4 of 74 patients (5%) (hemizygous in 3, homozygous in 1 patient). Although the complete remission (CR) rate was similar (79% vs. 50%; P = 0.187), CR duration (10 vs. 46 weeks; P < 0.001), event free survival rate (EFS; 6 vs. 85 weeks; P < 0.004) and overall survival rate (11 vs. 86 weeks; P = 0.001) were significantly shorter in patients with deletions of p16(INK4a)/p14(ARF) and/or p15(INK4b). Thirty-seven (47%) of 79 patients studied for MDM-2 showed increased MDM-2 expression. These patients had a significantly shorter EFS rate (50 vs. 64 weeks; P = 0.023) and a trend for shorter CR duration (24 vs. 53 weeks; P = 0.07). Overall survival rate was not significantly different (50 vs. 84 weeks; P = 0.136). CONCLUSIONS: The authors concluded that 1) deletions of p16(INK4a)/p14(ARF) and/or p15(INK4b) occur with low incidence in patients with AML; 2) patients with deletions of p16(INK4a)/p14(ARF) and/or p15(INK4b) have a significantly shorter CR duration, EFS rate, and overall survival rate than do patients without deletions; (3) overexpression of MDM-2 is common in AML and is associated with shorter CR duration and EFS rate. Mechanisms other than p14(ARF) deletion are responsible for MDM-2 overexpression, and this overexpression may play a role in the biology of the disease.

Adult↗

PubMed2000

Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes.

Angiogenesis has been associated with the growth, dissemination, and metastasis of solid tumors. The aims of this study were to evaluate the vascularity and the levels of angiogenic factors in patients with acute and chronic leukemias and myelodysplastic syndromes (MDS). The numbers of blood vessels were measured in 145 bone marrow biopsies and the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis growth factor-alpha (TNF-alpha), tumor growth factor-alpha (TGF-alpha), and hepatocyte growth factor (HGF) were determined in 417 plasma samples. Except for chronic lymphocytic leukemia (CLL), vascularity was significantly higher in all leukemias and MDS compared with control bone marrows. The highest number of blood vessels and largest vascular area were found in chronic myeloid leukemia (CML). VEGF, bFGF, and HGF plasma levels were significantly increased in acute myeloid leukemia (AML), CML, CLL, chronic myelomonocytic leukemia (CMML), and MDS. HGF, TNF-alpha, and bFGF but not VEGF were significantly increased in acute lymphoblastic leukemia (ALL). TNF-alpha levels were significantly increased in all diseases except for AML and MDS. No significant increase was found in TGF-alpha in any leukemia or MDS. The highest plasma levels of VEGF were in CML, and the highest plasma levels of bFGF were in CLL. The levels of HGF were highest in CMML. These data suggest that vascularity and angiogenic factors are increased in leukemias and MDS and may play a role in the leukemogenic process.

Acute Disease↗