Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
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To elucidate the clinical and biological features of childhood acute myeloid leukemia (AML) with the t(8;21), we reviewed the records of patients with AML treated at St Jude Children's Research Hospital over a 17-year period (1980 to 1996). Of 298 patients with AML, 40 (13%) had blast cells that contained the t(8;21). This translocation was associated with a high frequency of French-American-British M2 morphology (82%) and the presence of granulocytic sarcoma (23%). Molecular analysis detected the AML1-ETO fusion transcript in all 25 cases with the t(8;21) tested, but failed to identify additional cases with AML1-ETO among the 127 cases with other cytogenetic findings. Compared to patients with other genetic abnormalities, those with the t(8;21) were less likely to have internal tandem duplications of the FLT3 gene (none of 10 vs 16 of 68). The 6-year overall survival estimate was 55% +/- 9% and the event-free survival estimate, 33% +/- 7%. Of the clinical and biological features examined, only gender was prognostically significant: the 6-year overall survival estimate for males was 68% +/- 10%, compared to 33% +/- 11 for female patients (P = 0.03). Treatment outcome was not influenced by the chemotherapy regimen used or by the use of autologous hematopoietic stem cell transplantation. These results suggest that t(8;21)-positive AML represents a heterogeneous disease with variable outcome. The reported favorable outcome for t(8;21)-positive AML in other studies may be due to the use of high-dose cytarabine.
Leukemia 2002 Oct
PMID:Characteristics and outcome of t(8;21)-positive childhood acute myeloid leukemia: a single institution's experience. 1235 59

Alterations in the FLT3 gene, including internal tandem duplications (ITDs) and D835 mutations occur frequently in acute myelogenous leukemia. We investigated the prevalence and clinico-biological correlations of FLT3 ITDs and D835 mutations in 90 patients with acute promyelocytic leukemia (APL) receiving the AIDA protocol. Twenty patients in which both presentation and relapse material was available were analyzed sequentially. Thirty-three patients (37%) harbored the ITD, and seven (7.7%) the D835 mutation in blasts obtained at diagnosis. Presence of ITDs was strongly associated with high WBC count (P = 0.0001), M3 variant (P = 0.0004), and the short (BCR3) PML/RARalpha isoform (P = 0.003). There was no difference in response to induction in the two ITD+ve and ITD-ve groups, while a trend towards inferior outcome was observed for ITD+ve cases when analyzing disease-free survival (DFS) and relapse risk (RR). These differences, however, did not reach statistical significance. Sequential studies showed variable patterns in diagnostic and relapse material, ie ITD (-ve/-ve, +ve/+ve, +ve/-ve, -ve/+ve) and D835 (-ve/-ve, +ve/-ve, -ve/+ve). Our results indicate that FLT3 alterations are associated in APL with more aggressive clinical features and suggest that these lesions may not play a major role in leukemia progression.
Leukemia 2002 Nov
PMID:Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. 1239 60

Although many acute myeloid leukemia (AML) colony-forming cells (CFCs) and long-term culture-initiating cells (LTC-ICs) directly isolated from patients are actively cycling, quiescent progenitors are present in most samples. In the current study, (3)H-thymidine ((3)H-Tdr) suicide assays demonstrated that most NOD/SCID mouse leukemia-initiating cells (NOD/SL-ICs) are quiescent in 6 of 7 AML samples. AML cells in G(0), G(1), and S/G(2)+M were isolated from 4 of these samples using Hoechst 33342/pyroninY staining and cell sorting. The progenitor content of each subpopulation was consistent with the (3)H-Tdr suicide results, with NOD/SL-ICs found almost exclusively among G(0) cells while the cycling status of AML CFCs and LTC-ICs was more heterogeneous. Interestingly, after 72 hours in serum-free culture with or without Steel factor (SF), Flt-3 ligand (FL), and interleukin-3 (IL-3), most G(0) AML cells entered active cell cycle (percentage of AML cells remaining in G(0) at 72 hours, 1.2% to 37%, and 0% to 7.6% in cultures without and with growth factors [GFs], respectively) while G(0) cells from normal lineage-depleted bone marrow remained quiescent in the absence of GF. All 4 AML samples showed evidence of autocrine production of 2 or more of SF, FL, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, 3 of 4 samples contained an internal tandem duplication of the FLT3 gene. In summary, quiescent leukemic cells, including NOD/SL-ICs, are present in most AML patients. Their spontaneous entry into active cell cycle in short-term culture might be explained by the deregulated GF signaling present in many AMLs.
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PMID:Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML). 1246 27

Somatic mutation of the FLT3 gene as an internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence causes constitutive tyrosine phosphorylation and activation. Tumor-specific DNA has been documented in the sera of patients with solid tumors even when it is in an early stage. We compared the detection of FLT3 ITD in DNA extracted from cells of bone marrow (BM) aspirations with DNA extracted from peripheral blood (PB) plasma in patients newly diagnosed with acute myeloid leukemia (AML; 85 patients), myelodysplastic syndrome (MDS; 16 patients), and acute lymphocytic leukemia (ALL; 16 patients). FLT3 ITD was detected in 18 (21%) AML samples and in one (6%) MDS sample in both cellular and plasma DNA but in none of the ALL samples. Hemizygous/homozygous FLT3 ITD was detected in five (28%) of the FLT3 ITD-positive AML using plasma DNA, whereas only four of these cases showed hemizygous/homozygous FLT3 ITD using cellular DNA. The presence of FLT3 ITD was associated with significantly shorter survival (P = 0.02) when only patients younger than 50 years of age (48 AML+MDS patients) were considered. This finding was independent of cytogenetics in this age group. However, patients with the FLT3 ITD hemizygous/homozygous phenotype had even shorter survival (P = <0.001). As expected, the presence of FLT3 ITD correlated with higher white blood cell (WBC) counts. These data demonstrate that plasma DNA is a reliable alternative resource for detecting FLT3ITD, especially the hemizygous/homozygous genotype. Furthermore, the data derived from this study support the notion that the presence of FLT3 ITD in conjunction with the absence of the wild-type FLT3 allele predicts an especially poor prognosis for patients with AML.
Leukemia 2003 Jan
PMID:Better detection of FLT3 internal tandem duplication using peripheral blood plasma DNA. 1252 67

Internal tandem duplications (ITD) and D835 point mutations of the receptor tyrosine kinase (RTK) FLT3 are found in a high proportion of cases with acute myeloid leukemia (AML). These genetic aberrations may lead to the constitutive activation of the receptor, thus providing the molecular basis for a persisting growth stimulus. We have screened 69 AML-derived cell lines for FLT3 mutations. Four of these cell lines showed ITD of the FLT3 gene, none carried a D835 point mutation. Two cell lines (MUTZ-11 and MV4-11) expressed exclusively the mutated allele, the other two cell lines (MOLM-13 and PL-21) displayed a mutated and the wild-type version of the gene. Although mutationally activated FLT3 is supposed to substitute for the stimulatory signal of a growth factor, one of these cell lines (MUTZ-11) was strictly cytokine-dependent. FLT3 transcripts were found in all four cell lines, but the constitutively phosphorylated receptor protein was clearly detectable only in cell line MV4-11, possibly explaining why MUTZ-11 cells were growth-factor dependent. Thus, not all FLT3 ITD-positive cells express high levels of the active receptor protein, a finding that might be of relevance for a possible future application of a kinase inhibitor as therapeutic agent. It had been described that STAT-5 phosphorylation was part of the FLT3 signalling chain and that STAT-5 molecules were constitutively phosphorylated in FLT3 ITD-positive cells. Although we observed the constitutive phosphorylation of STAT-5 molecules in FLT3-mutant cells, FLT3 ligand (FL) did not induce STAT-5 phosphorylation in FLT3 wild-type cells. These results suggest that the signalling mechanisms of the mutated FL receptor differ at least to some extent from those conferred by wild-type FLT3. In conclusion, (1) not all cells with FLT3 ITD express significant amounts of the mutated receptor protein; (2) signals downstream from wild-type and mutant FLT3 receptors are not 100% identical; and (3) MV4-11 represents a model cell line for FLT3 ITD signalling.
Leukemia 2003 Jan
PMID:FLT3 mutations in acute myeloid leukemia cell lines. 1252 68

SCF is a potent pro-proliferative cytokine crucial for haematopoiesis, which binds to c-kit and activates its tyrosine kinase activity. Inactivating mutations of either SCF or c-kit have been described in mice and lead to increased sensitivity to treatment with ionising radiation. Imatinib is a tyrosine kinase inhibitor with high affinity for c-Abl, PDGFR and c-kit. In this study we investigated the effect of concomitant administration of imatinib and idarubicin, an anthracycline with haematosuppressive activity, in nu/nu mice and murine bone marrow cells. Double-treated animals showed significantly increased mortality compared to mice that received imatinib or idarubicin alone only when idarubicin and imatinib were given simultaneously. The combined treatment induced a more severe neutropenia with a slower recovery when compared to mice treated with idarubicin alone. The myeloid metaplasia usually observed in the spleen after idarubicin treatment was absent in mice co-treated with imatinib. Bone marrow from double-treated animals also showed decreased numbers of megakaryocytes and myeloid precursor cells. In vitro culture of murine bone marrow cells in the presence of imatinib inhibited SCF-induced proliferation and recovery from treatment with idarubicin. Our results indicate that the simultaneous administration of imatinib enhances idarubicin-induced haematopoietic toxicity in vivo and in vitro.
Leukemia 2003 Feb
PMID:Effect of imatinib on haematopoietic recovery following idarubicin exposure. 1496 Oct 27

In response to PMA treatment K562 myelogenous leukemia cells undergo megakaryocytic differentiation, which is dependent on prolonged ERK activation and is characterized by growth arrest, upregulation of CD41 and IL-6, and, finally, by characteristic changes in cell morphology. The tyrosine phosphatase HePTP was recently demonstrated to regulate ERK activity and changes in HePTP expression have been associated with hematopoietic malignancies. Here, we have studied the function of HePTP during PMA-induced megakaryocytic differentiation of K562 cells. Overexpression of HePTP or inhibition of HePTP expression with antisense cDNA had no effect on PMA-induced cell cycle arrest or upregulation of cyclin D in K562 cells. The expression of megakaryocytic markers such as CD41 and IL6, however, were highly reduced in cells overexpressing HePTP, due to reduced ERK activation, and the cells were impaired in their ability to differentiate. Compared to control cells, HePTP antisense expressing cells did not show increased basal or PMA-induced ERK activity. However, antisense inhibition of HePTP enhanced nuclear translocation of ERK and the expression of the megakaryocytic markers CD41 and IL-6. Interestingly, like cells overexpressing HePTP, morphological differentiation was also impaired in HePTP antisense expressing cells. The results for the first time demonstrate that different aspects of megakaryocytic differentiation have distinct requirements for ERK activity. They further show that HePTP is involved in the regulation of nuclear translocation of ERK2 and that HePTP protein levels can modulate K562 cell differentiation.
Leukemia 2003 Feb
PMID:The protein tyrosine phosphatase HePTP regulates nuclear translocation of ERK2 and can modulate megakaryocytic differentiation of K562 cells. 1259 37

Neutrophils and monocytes/macrophages are derived from common progenitors, but exhibit markedly different lifespans. Differentiated neutrophils are short-lived and die rapidly by apoptosis, while monocytic cells are longer-lived. In this report we used the HL-60 cell line as a model system to identify differences in apoptotic pathways which might account for the differing lifespans of granulocytic vs monocytic cells. We observed that induction of granulocytic differentiation by retinoic acid led to robust activation of the executioner protease caspase-3, and early onset of apoptosis. By contrast, caspase-3 was not appreciably activated during phorbol 12-myristate 13-acetate (PMA)-induced monocytic differentiation, and apoptosis was delayed in these cells. Since the activation of caspase-3 is inhibited by members of the inhibitor of apoptosis (IAP) and Bcl-2 protein families, we investigated the expression of anti-apoptotic members of these families. Induction of monocytic differentiation led to marked upregulation of the IAP protein XIAP, as well as the Bcl-2 family member Bcl-X(L). During granulocytic differentiation the levels of XIAP progressively declined, while Bcl-X(L) levels remained unchanged. A different IAP protein, survivin, was downregulated during differentiation along either lineage, as was expression of Bcl-2. The upregulation of Bcl-X(L) during monocytic differentiation coincided with phosphorylation/activation of STAT3, a known activator of bcl-X gene transcription. Moreover, Bcl-X(L) upregulation was dependent on MEK/ERK signaling. Upregulation of XIAP proceeded in a MEK/ERK-independent fashion. Treatment with antisense Bcl-X(L) or XIAP oligonucleotides resulted in significant loss of viability in cells differentiating along the monocytic lineage. Together, these findings indicate that the levels of XIAP and Bcl-X(L) are regulated by distinct pathways during monocytic differentiation, and that upregulation of these proteins contributes to the increased longevity of cells in the monocytic lineage.
Leukemia 2003 Feb
PMID:Differential activation of apoptosis regulatory pathways during monocytic vs granulocytic differentiation: a requirement for Bcl-X(L)and XIAP in the prolonged survival of monocytic cells. 1259 39

Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) have been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis. We recently showed that certain 'liquid' tumors such as leukemia not only produce VEGF, but also express functional VEGFR, resulting in an autocrine loop for tumor growth and propagation. A chimeric anti-VEGFR2 (or kinase insert domain-containing receptor, KDR) antibody, IMC-1C11, was shown to be able to inhibit VEGF-induced proliferation of human leukemia cells in vitro, and to prolong survival of nonobese diabetic-severe combined immune deficient (NOD-SCID) mice inoculated with human leukemia cells. Here we produced two fully human anti-KDR antibodies (IgG1), IMC-2C6 and IMC-1121, from Fab fragments originally isolated from a large antibody phage display library. These antibodies bind specifically to KDR with high affinities: 50 and 200 pM for IMC-1121 and IMC-2C6, respectively, as compared to 270 pM for IMC-1C11. Like IMC-1C11, both human antibodies block VEGF/KDR interaction with an IC(50) of approximately 1 nM, but IMC-1121 is a more potent inhibitor to VEGF-stimulated proliferation of human endothelial cells. These anti-KDR antibodies strongly inhibited VEGF-induced migration of human leukemia cells in vitro, and when administered in vivo, significantly prolonged survival of NOD-SCID mice inoculated with human leukemia cells. It is noteworthy that the mice treated with antibody of the highest affinity, IMC-1121, survived the longest period of time, followed by mice treated with IMC-2C6 and IMC-1C11. Taken together, our data suggest that anti-KDR antibodies may have broad applications in the treatment of both solid tumors and leukemia. It further underscores the efforts to identify antibodies of high affinity for enhanced antiangiogenic and antitumor activities.
Leukemia 2003 Mar
PMID:Inhibition of human leukemia in an animal model with human antibodies directed against vascular endothelial growth factor receptor 2. Correlation between antibody affinity and biological activity. 1264 50

Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of human hematologic malignancies. An internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence of the FLT3 gene (FLT3-ITD) is found in 20-25% of adult acute myeloid leukemia (AML) and at a lower frequency in childhood AML. FLT3-ITD is associated with leukocytosis and a poor prognosis, especially in patients with normal karyotype. Recently, there have been three reports on point mutations at codon 835 of the FLT3 gene (D835 mutations) in adult AML. These mutations are located in the activation loop of the second tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD). The clinical and prognostic relevance of the TKD mutations is less clear. To the best of our knowledge, there has been no report to describe FLT3-TKD mutations in childhood AML. In this pediatric series, FLT3-TKD mutations occurred in three of 91 patients (3.3%), an incidence significantly lower than that of FLT3-ITD (14 of 91 patients, 15.4%) in the same cohort of patients. None of them had both FLT3-TKD and FLT3-ITD mutations. Sequence analysis showed one each of D835 Y, D835 V, and D835 H. Of the three patients carrying FLT3-TKD, two had AML-M3 with one each of L- and V-type PML-RARalpha, and another one had AML-M2 with AML1-ETO. None of our patients with FLT3-TKD had leukocytosis at diagnosis. At bone marrow relapse, one of the four patients examined acquired FLT3-ITD mutation and none gained FLT3-TKD mutation.
Leukemia 2003 May
PMID:FLT3-TKD mutation in childhood acute myeloid leukemia. 1275 Jul 1


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