scholarly journals Block of C/EBPα function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations

2006 ◽  
Vol 203 (2) ◽  
pp. 371-381 ◽  
Author(s):  
Hanna S. Radomska ◽  
Daniela S. Bassères ◽  
Rui Zheng ◽  
Pu Zhang ◽  
Tajhal Dayaram ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Myelogenous Leukemia ◽  
Granulocytic Differentiation ◽  
Extracellular Signal Regulated Kinase ◽  
Activating Mutations ◽  
Flt3 Inhibitor ◽  
Extracellular Signal ◽  
Enhancer Binding Protein ◽  
Acute Myelogenous ◽  
Differentiation Block

Mutations constitutively activating FLT3 kinase are detected in ∼30% of acute myelogenous leukemia (AML) patients and affect downstream pathways such as extracellular signal–regulated kinase (ERK)1/2. We found that activation of FLT3 in human AML inhibits CCAAT/enhancer binding protein α (C/EBPα) function by ERK1/2-mediated phosphorylation, which may explain the differentiation block of leukemic blasts. In MV4;11 cells, pharmacological inhibition of either FLT3 or MEK1 leads to granulocytic differentiation. Differentiation of MV4;11 cells was also observed when C/EBPα mutated at serine 21 to alanine (S21A) was stably expressed. In contrast, there was no effect when serine 21 was mutated to aspartate (S21D), which mimics phosphorylation of C/EBPα. Thus, our results suggest that therapies targeting the MEK/ERK cascade or development of protein therapies based on transduction of constitutively active C/EBPα may prove effective in treatment of FLT3 mutant leukemias resistant to the FLT3 inhibitor therapies.

Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPα expression

Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1883-1890 ◽  
Author(s):  
Rui Zheng ◽  
Alan D. Friedman ◽  
Mark Levis ◽  
Li Li ◽  
Edward G. Weir ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Tandem Duplication ◽  
Myeloid Differentiation ◽  
Internal Tandem Duplication ◽  
Activating Mutations ◽  
Flt3 Inhibitor ◽  
Enhancer Binding Protein ◽  
Differentiation Block ◽  
Proliferative Signaling

AbstractConstitutively activating mutations of FMS-like tyrosine kinase 3 (FLT3) occur in approximately one third of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Altered FLT3 signaling leads to antiapoptotic and proliferative signaling pathways. We recently showed that these mutations can also contribute to the differentiation arrest that characterizes leukemia. In this report we investigated the mechanism by which internal tandem duplication (ITD) mutation of FLT3 signaling blocks differentiation. Normally, myeloid differentiation requires the induction of CCAAT/enhancer-binding protein α (C/EBPα) and PU.1 expression. Expression of both genes was repressed by FLT3/ITD signaling in 32Dcl3 (32D) cells and this repression was overcome by treatment with a FLT3 inhibitor, allowing differentiation to proceed. We also observed increased expression of C/EBPα and PU.1 accompanied by signs of differentiation in 2 of 3 primary AML samples from patients with FLT3/ITD mutations receiving a FLT3 inhibitor, CEP-701, as part of a clinical trial. Forced expression of C/EBPα was also able to overcome FLT3/ITD-mediated differentiation block, further proving the importance of C/EBPα in this process.

Target proteins of C/EBPαp30 in AML: C/EBPαp30 enhances sumoylation of C/EBPαp42 via up-regulation of Ubc9

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3301-3309 ◽  
Author(s):  
Mulu Geletu ◽  
Mumtaz Y. Balkhi ◽  
Abdul A. Peer Zada ◽  
Maximilian Christopeit ◽  
John A. Pulikkan ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Dominant Negative ◽  
Granulocytic Differentiation ◽  
Target Proteins ◽  
Human Cd34 ◽  
Enhancer Binding Protein ◽  
Cd34 Cells ◽  
Proteomics Approach ◽  
Differentiation Block ◽  
Stimulating Factor

Abstract CCAAT/enhancer-binding protein α (C/EBPα) is a critical regulator for early myeloid differentiation. Mutations in C/EBPα occur in 10% of patients with acute myeloid leukemia (AML), leading to the expression of a 30-kDa dominant-negative isoform (C/EBPαp30). In the present study, using a global proteomics approach to identify the target proteins of C/EBPαp30, we show that Ubc9, an E2-conjugating enzyme essential for sumoylation, is increased in its expression when C/EBPαp30 is induced. We confirmed the increased expression of Ubc9 in patients with AML with C/EBPαp30 mutations compared with other subtypes. We further confirmed that the increase of Ubc9 expression was mediated through increased transcription. Furthermore, we show that Ubc9-mediated enhanced sumoylation of C/EBPαp42 decreases the transactivation capacity on a minimal C/EBPα promoter. Importantly, overexpression of C/EBPαp30 in granulocyte colony-stimulating factor (G-CSF)–stimulated human CD34+ cells leads to a differentiation block, which was overcome by the siRNA-mediated silencing of Ubc9. In summary, our data indicate that Ubc9 is an important C/EBPαp30 target through which C/EBPαp30 enhances the sumoylation of C/EBPαp42 to inhibit granulocytic differentiation.

scholarly journals Clinicohematological Study of Thrombocytosis in Children

2014 ◽  
Vol 2014 ◽  
pp. 1-4 ◽  
Author(s):  
Nathiya Subramaniam ◽  
Suneel Mundkur ◽  
Pushpa Kini ◽  
Nalini Bhaskaranand ◽  
Shrikiran Aroor
Keyword(s):  
Platelet Count ◽  
Myeloid Leukemia ◽  
Prospective Observational Study ◽  
Myelogenous Leukemia ◽  
Distribution Width ◽  
Female Ratio ◽  
Reactive Thrombocytosis ◽  
Acute Myelogenous ◽  
Male To Female ◽  
Primary Thrombocytosis

Introduction. Primary thrombocytosis is very rare in children; reactive thrombocytosis is frequently observed in children with infections, anemia, and many other causes. Aims and Objectives. To identify the etiology of thrombocytosis in children and to analyze platelet indices (MPV, PDW, and PCT) in children with thrombocytosis. Study Design. A prospective observational study. Material and Methods. A total of 1000 patients with thrombocytosis (platelet > 400×109/L) were studied over a period of 2 years. Platelet distribution width (PDW), mean platelet volume (MPV), and plateletcrit (PCT) were noted. Results. Of 1000 patients, 99.8% had secondary thrombocytosis and only two children had primary thrombocytosis (chronic myeloid leukemia and acute myelogenous leukemia, M7). The majority of the children belonged to the age group of 1month to 2 years (39.7%) and male to female ratio was 1.6 : 1. Infection with anemia (48.3%) was the most common cause of secondary thrombocytosis followed by iron deficiency alone (17.2%) and infection alone (16.2%). Respiratory infection (28.3%) was the predominant infectious cause observed. Thrombocytosis was commonly associated with IDA among all causes of anemia and severity of thrombocytosis increased with severity of anemia (P=0.021). With increasing platelet count, there was a decrease in MPV (<0.001). Platelet count and mean PDW among children with infection and anemia were significantly higher than those among children with infection alone and anemia alone. None were observed to have thromboembolic manifestations. Conclusions. Primary thrombocytosis is extremely rare in children than secondary thrombocytosis. Infections in association with anemia are most commonly associated with reactive thrombocytosis and severity of thrombocytosis increases with severity of anemia.

scholarly journals Targeted α particle immunotherapy for myeloid leukemia

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1233-1239 ◽  
Author(s):  
Joseph G. Jurcic ◽  
Steven M. Larson ◽  
George Sgouros ◽  
Michael R. McDevitt ◽  
Ronald D. Finn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Absorbed Dose ◽  
Myelogenous Leukemia ◽  
Whole Body ◽  
Hematopoietic Stem ◽  
Acute Myelogenous ◽  
Antigen System ◽  
High Doses ◽  
Nonspecific Cytotoxicity

Unlike β particle–emitting isotopes, α emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the β-emitters 131I and 90Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of β-emitting constructs, the α-emitting isotope 213Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg 213Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the 213Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with β-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of 213Bi-HuM195, and it is the first proof-of-concept for systemic targeted α particle immunotherapy in humans.

Experience With 2-Chlorodeoxyadenosine in Previously Untreated Children With Newly Diagnosed Acute Myeloid Leukemia and Myelodysplastic Diseases

2001 ◽  
Vol 19 (11) ◽  
pp. 2804-2811 ◽  
Author(s):  
R. A. Krance ◽  
C. A. Hurwitz ◽  
D. R. Head ◽  
S. C. Raimondi ◽  
F. G. Behm ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Myelogenous Leukemia ◽  
Remission Induction ◽  
Allogeneic Bone ◽  
Event Free Survival ◽  
Free Survival ◽  
Secondary Aml ◽  
Acute Myelogenous ◽  
French American British

PURPOSE: To develop more effective chemotherapy regimens for childhood acute myelogenous leukemia (AML). PATIENTS AND METHODS: Between June 1991 and December 1996, we administered the nucleoside analog 2-chlorodeoxyadenosine (2-CDA) to 73 children with primary AML and 20 children with secondary AML or myelodysplastic syndrome (MDS). Patients received one or two 5-day courses of 2-CDA (8.9 mg/m2/d) given by continuous infusion. All patients then received one to three courses of daunomycin, cytarabine, and etoposide (DAV) remission induction therapy. RESULTS: Seventy-two patients with primary AML were assessable for response. Their rate of complete remission (CR) was 24% after one course of 2-CDA, 40% after two courses of 2-CDA, and 78% after DAV therapy. Of the 57 patients who entered CR, 11 subsequently underwent allogeneic bone marrow transplantation (BMT), and 40 underwent autologous BMT. Twenty-nine patients remain in continuous CR after BMT. Two patients remain in CR after chemotherapy only. The 5-year event-free survival (EFS) estimate was 40% (SE = 0.080%). Patients with French-American-British (FAB) M5 AML had a higher rate of CR after treatment with 2-CDA (45% after one course and 70.6% after two courses) than did others (P = .002). In contrast, no patient with FAB M7 AML (n = 10) entered CR after treatment with 2-CDA. Similarly, no patient with primary MDS (n = 6) responded to 2-CDA. Seven patients with secondary AML or MDS (n = 14) had a partial response to one course of 2-CDA. CONCLUSION: This agent was well tolerated, and its toxicity was acceptable. Future trials should examine the effectiveness of 2-CDA given in combination with other agents effective against AML.

scholarly journals Treatment of newly diagnosed acute myelogenous leukemia with granulocyte-macrophage colony-stimulating factor (GM-CSF) before and during continuous-infusion high-dose ara-C + daunorubicin: comparison to patients treated without GM-CSF

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2246-2255 ◽  
Author(s):  
E Estey ◽  
PF Thall ◽  
H Kantarjian ◽  
S O'Brien ◽  
CA Koller ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Newly Diagnosed ◽  
Gm Csf ◽  
Negative Effect ◽  
Acute Myelogenous ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract We gave 56 patients with newly diagnosed acute myelogenous leukemia (AML) granulocyte-macrophage colony-stimulating factor (GM-CSF) 20 or 125 micrograms/m2 once daily subcutaneously before (for up to 8 days or until GM-CSF-related complications developed) and during, or only during (patients presenting with blast counts greater than 50,000 or other leukemia-related complications) ara-C (1.5 g/m2 daily x 4 by continuous infusion) and daunorubicin (45 mg/m2 daily x 3) chemotherapy. Because results seemed independent of GM-CSF schedule, we compared results in these 56 patients with results in 176 patients with newly diagnosed AML given the same dose and schedule of ara-C without GM-CSF (110 patients ara-C alone, 66 patients ara-C + amsacrine or mitoxantrone). Comparison involved fitting a logistic regression model predicting probability of complete remission (CR) and a Cox regression model to predict survival (most patients in all three studies were dead) with treatment included as a covariate in both analyses. After adjusting for other prognostically significant covariates [presence of an antecedent hematologic disorder, an Inv (16), t(8;21), or abnormalities of chromosomes 5 and/or 7, performance status, age, bilirubin], treatment with ara-C + daunorubicin + GM-CSF was predictive of both a lower CR rate and a lower survival probability. There were no treatment-covariate interactions, suggesting that the negative effect of this GM-CSF treatment regime was not an artifact of some imbalance in patient characteristics. The unadjusted Kaplan-Meier hazard rate of the ara-C + daunorubicin + GM-CSF group was not uniquely high during the initial 4 weeks after start of therapy, but was highest among the three treatment groups throughout weeks 5 to 16, suggesting that the negative effect of this treatment was not caused by acute toxicity. Patients who did not enter CR with this treatment tended to have persistent leukemia rather than prolonged marrow aplasia, suggesting that this treatment and, in particular, GM-CSF may increase resistance of myeloid leukemia cells to chemotherapy. To date, relapse rates are similar in all three groups (P = .43) (as are survival rates once patients are in CR) but much of the remission duration data is heavily censored, unlike the survival data. Our results suggest caution in the use of GM-CSF to sensitize myeloid leukemia cells to daunorubicin + ara- C chemotherapy.

scholarly journals Translocations and deletions of 5q13.1 in myelodysplasia and acute myelogenous leukemia: evidence for a novel critical locus

Blood ◽  
1996 ◽  
Vol 88 (6) ◽  
pp. 2259-2266 ◽  
Author(s):  
J Fairman ◽  
RY Wang ◽  
H Liang ◽  
L Zhao ◽  
D Saltman ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Interstitial Deletion ◽  
Negative Regulator ◽  
Myelogenous Leukemia ◽  
Chromosome 5 ◽  
Entire Chromosome ◽  
Acute Myelogenous ◽  
Paracentric Inversions ◽  
Acute Myeloid

Acquired partial and complete deletions of chromosome 5 (5q-, -5) are common cytogenetic anomalies associated with myelodysplasia (MDS) and acute myeloid leukemia (AML). A critical region of consistent loss at 5q31.1 (in > 90% of cases) has led us and others to postulate the presence of a key negative regulator(s) of leukemogenesis. Although the interstitial deletion limits vary among patients, del(5) (q13q33) and del(5)(q13q35) constitute major subsets. Furthermore, it is not rare to encounter deletions, translocations, or paracentric inversions involving 5q11 to 5q13, which indicates inactivation or disruption of important gene(s) at that locus. In this report, we have localized a novel locus at 5q13.1 to a 2.0-Mb interval between the anonymous markers D5S672 and GATA-P1804. This locus resided within the region of loss in 12 of 27 patients with anomalies of chromosome 5; one of these cases had apparent retention of both alleles of all the telomeric loci. Fluorescence in situ hybridization (FISH) studies demonstrate that the AML cell line ML3 is disrupted at 5q13.1 by a translocation involving chromosome 3, with apparent retention of the entire chromosome 5 sequence. Our results suggest that this novel proximal locus encodes a critical gene that may be deleted or disrupted in a subset of MDS/AML patients with chromosome 5 anomalies.

scholarly journals Activating Mutations of the Noonan Syndrome-Associated SHP2/PTPN11 Gene in Human Solid Tumors and Adult Acute Myelogenous Leukemia

2004 ◽  
Vol 64 (24) ◽  
pp. 8816-8820 ◽  
Author(s):  
Mohamed Bentires-Alj ◽  
J. Guillermo Paez ◽  
Frank S. David ◽  
Heike Keilhack ◽  
Balazs Halmos ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Acute Myelogenous Leukemia ◽  
Noonan Syndrome ◽  
Myelogenous Leukemia ◽  
Ptpn11 Gene ◽  
Activating Mutations ◽  
Human Solid Tumors ◽  
Acute Myelogenous
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