RUNX1 mutations are frequent in de novo AML with noncomplex karyotype and confer an unfavorable prognosis

Blood ◽  
2011 ◽  
Vol 117 (8) ◽  
pp. 2348-2357 ◽  
Author(s):  
Susanne Schnittger ◽  
Frank Dicker ◽  
Wolfgang Kern ◽  
Nicole Wendland ◽  
Jana Sundermann ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Tandem Duplication ◽  
De Novo ◽  
Molecular Genetic ◽  
Normal Karyotype ◽  
Internal Tandem Duplication ◽  
Free Survival ◽  
De Novo Aml ◽  
The Individual ◽  
French American British

Abstract Analyses of 164 RUNX1 mutations (RUNX1mut) in 147 of 449 patients (32.7%) with normal karyotype or noncomplex chromosomal imbalances were performed. RUNX1mut were most frequent in acute myeloid leukemia French-American-British classification M0 (65.2%) followed by M2 (32.4%) and M1 (30.2%). Considering cytogenetics, RUNX1mut were most frequent in cases with +13 (27 of 30, 90%), whereas frequencies were similar in other cytogenetic groups (26%-36%). The molecular genetic markers most frequently associated with RUNX1mut were partial tandem duplication in the MLL gene (19.7%), internal tandem duplication in the FLT3 gene (FLT3-ITD; 16.3%), and NRAS mutations (9.5%). Patients with RUNX1mut had shorter overall and event-free survival compared with RUNX1 wild-type cases (median, 378 days vs not reached, P = .003; and median, 285 vs 450 days, P = .003, respectively). In addition, it was shown that the adverse effect of RUNX1 was independent of the adverse effect of FLT3-ITD as well as of the high frequency of prognostically favorable NPM1mut and CEBPAmut in the RUNX1wt group. No effect of the type or localization of the individual RUNX1 mutations was observed. Multivariate analysis showed independent prognostic relevance for overall survival for RUNX1mut (P = .029), FLT3-ITD (P = .003), age (P < .001), and white blood cell count (P < .002).

FLT3 Internal Tandem Duplications in Adults with De Novo Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4430-4430
Author(s):  
Sandra G. Xavier ◽  
Rocío Hassan ◽  
Nelma C.D. Clementino ◽  
Daniel G. Tabak ◽  
Nelson Spector ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
De Novo ◽  
Univariate Analysis ◽  
Internal Tandem Duplication ◽  
Hematopoietic Stem ◽  
Proliferation And Differentiation ◽  
Polymerase Chain ◽  
De Novo Aml ◽  
Tandem Duplications

Abstract FLT3 is a receptor tyrosine kinase involved in the proliferation and differentiation of hematopoietic stem cells. Recently, internal tandem duplication (ITD) mutations of the FLT3 gene have been described in patients with AML and associated with a poor prognosis. The aim of this study was to analyze the prevalence of FLT3-ITD in a series of 90 adults with de novo AML and correlate the presence of this mutation with biological characteristics and clinical response. We analyzed diagnostic peripheral blood or bone marrow specimens from 43 women and 47 men, with a median age of 38 years (16–83). Polymerase chain reaction was performed on genomic DNA using previously published primers for exons 11 and 12. An FLT3-ITD was found in 22/89 patients (25%). It was present in 37% (9/24) of the patients with acute promyelocytic leukemia (APL) and in only 20% (13/65) of the patients with non-M3-AML (p=0.07). The FLT3-ITD was not detected in patients with M6 (n=1) and M7-AML (n=3), nor in patients with the AML1-ETO (n=2) or with the CBFb-MYH11 (n=4) fusion genes. The median WBC counts were higher in FLT3-ITD patients than in those without the mutation (37 X 109/L vs. 27 X 109/L, p=0.43). In APL, FLT3-ITD was found in 5 out of 6 patients with the short PML-RARa isoform, but in only 4 out of 18 patients with the non-short isoform (p=0.01). Univariate analysis showed an association between the presence of FLT3-ITD and both a lower complete remission (CR) rate (41% vs. 64%; p=0.05) and a shorter overall survival (14% vs. 34%; p=0.03). However, FLT3-ITD was not associated with the CR rate (p=0.18) or the OS (p=0.07) in the multivariate analysis. The clinical significance of FLT3-ITD in adult AML remains uncertain, and further investigation is clearly warranted.

Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML)

Blood ◽  
2003 ◽  
Vol 101 (6) ◽  
pp. 2125-2131 ◽  
Author(s):  
Giovanni Del Poeta ◽  
Adriano Venditti ◽  
Maria Ilaria Del Principe ◽  
Luca Maurillo ◽  
Francesco Buccisano ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Disease Free Survival ◽  
Spontaneous Apoptosis ◽  
Free Survival ◽  
De Novo Aml ◽  
French American British ◽  
Disease Free ◽  
Acute Myeloid

The inability to undergo apoptosis is a crucial mechanism of multidrug resistance in acute myeloid leukemia (AML), and the analysis of mitochondrial apoptotic proteins may represent a significant prognostic tool to predict outcome. Bcl-2 and Bax oncoproteins were evaluated in 255 de novo AML patients (pts) by flow cytometry using an anti–bcl-2 monoclonal antibody (MoAb) and an anti-bax MoAb. The results were expressed as an index (bax/bcl-2) obtained by dividing bax mean fluorescence intensity (MFI) and bcl-2 MFI. Lower bax/bcl-2 ratio was associated with French-American-British (FAB) M0-M1 classes (P = .000 01) and CD34 more than 20% (P < .000 01). There were striking inverse correlations between CD34 or CD117 MFI and bax/bcl-2 values (r = −.40, P < .000 001 andr = −.29, P = .000 002), confirming that immaturity is consistent with this index. Moreover, lower bax/bcl-2 levels were correlated with poor-risk cytogenetics (P = .0002). A significant higher complete remission (CR) rate was found in pts with higher bax/bcl-2 levels (79% versus 45%; P = .000 01). Also, both a longer overall survival (OS) and disease-free survival (DFS) were observed in pts with higher bax/bcl-2 levels (P = .000 01 and = .019). Noteworthy, bax/bcl-2 levels accurately predicted the clinical response and outcome of pts with normal or unknown cytogenetics. Indeed, within this subset of 147 pts, higher bax/bcl-2 ratio was significantly associated both with a higher CR rate (86% versus 42%;P < .000 01) and a longer OS (P = .0016). The independent prognostic value of bax/bcl-2 ratio was confirmed in multivariate analysis. Therefore, mitochondrial oncoproteins, such as bcl-2 and bax, represent both sensitive indicators of clinical outcome and potential targets of novel proapoptotic molecules in order to circumvent chemoresistance.

FLT3 Internal Tandem Duplication in Acute Myeloid Leukemia with Normal Karyotype

2007 ◽  
Vol 42 (3) ◽  
pp. 250 ◽  
Author(s):  
Sang-Ho Kim ◽  
Yeo-Kyeoung Kim ◽  
Il-Kwon Lee ◽  
Deog-Yeon Jo ◽  
Jong-Ho Won ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Normal Karyotype ◽  
Internal Tandem Duplication ◽  
Flt3 Internal Tandem Duplication ◽  
Acute Myeloid

scholarly journals Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia

Blood ◽  
1992 ◽  
Vol 80 (11) ◽  
pp. 2873-2882 ◽  
Author(s):  
OI Olopade ◽  
M Thangavelu ◽  
RA Larson ◽  
R Mick ◽  
A Kowal-Vern ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Normal Karyotype ◽  
Intensive Chemotherapy ◽  
Trisomy 8 ◽  
Cytogenetic Abnormalities ◽  
Favorable Prognosis ◽  
Multiple Abnormalities ◽  
French American British

Abstract We have performed a retrospective analysis of the clinical, morphologic, and cytogenetic findings in 26 patients diagnosed between January 1969 and September 1991 with acute erythroblastic leukemia de novo (EL or AML-M6). Clonal chromosomal abnormalities were found in 20 (77%) patients (95% confidence interval [CI], 61% to 93%). Loss of all or part of the long arm (q) of chromosomes 5 and/or 7 was observed in 17 (65%) patients (95% CI, 47% to 83%). In addition, the karyotypes were often complex, with multiple abnormalities and subclones. Among the remaining nine patients, six had a normal karyotype and one each had trisomy 8, t(3;3), or t(3;5). The overall frequency of abnormalities of chromosomes 5 and/or 7 observed in our M6 patients is similar to that observed in our patients with therapy-related acute myeloid leukemia (t-AML; 99 of 129 patients, 77%), but substantially higher than that noted in our other patients with AML de novo (French- American-British [FAB] subtypes M1-M5: 52 of 334 patients, 16%). Our M6 patients with abnormalities of chromosomes 5 and/or 7 were older and had a shorter median survival (16 v 77 weeks [P = .005]) than did the M6 patients without these abnormalities. We found no correlation between morphologic features and either cytogenetic abnormalities or clinical outcome. Of note was the finding that the percentage of myeloblasts, which may account for only a small fraction of the total marrow elements when the revised FAB criteria are applied, had no bearing on prognosis. We conclude that acute erythroblastic leukemia, when defined by morphologic criteria, consists of two distinctive subgroups: one group tends to be older, has complex cytogenetic abnormalities, especially of chromosomes 5 and/or 7, and shares biologic and clinical features with t-AML; the other group, with simple or no detectable cytogenetic abnormalities, has a more favorable prognosis when treated with intensive chemotherapy.

Clinical relevance of P-glycoprotein expression in de novo acute myeloid leukemia

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1997-2004 ◽  
Author(s):  
G Del Poeta ◽  
R Stasi ◽  
G Aronica ◽  
A Venditti ◽  
MC Cox ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
Free Survival ◽  
Negative Phenotype ◽  
Acute Myeloid

Abstract Cytofluorimetric detection of the multidrug resistance (MDR)-associated membrane protein (P-170) was performed at the time of diagnosis in 158 patients with acute myeloid leukemia using the C219 monoclonal antibody (MoAb). In 108 of these cases the JSB1 MoAb was also tested. An improved histogram subtraction analysis, based on curve fitting and statistical test was applied to distinguish antigen-positive from antigen-negative cells. A marker was considered positive when more than 20% of the cells were stained. At onset, P-170 was detected in 43% of cases with C219 and in 73% of cases with JSB1. There was a strict correlation between C219 and JSB1 positivity, as all C219+ cases were also positive for JSB1 MoAb (P < .001). No relationship was found between sex, age, organomegaly, and MDR phenotype. Significant correlation was found between CD7 and both C219 and JSB1 expression (P < .001 and .001, respectively). C219-negative phenotype was more often associated with a normal karyotype (24 of 55 with P = .030). Rhodamine 123 (Rh123) staining and flow cytometry analysis showed a significantly decreased mean fluorescence in 51 C219+ and 38 JSB1+ patients compared to 42 MDR negative ones (P < .001). The rate of first complete remission (CR) differed both between C219+ and C219- cases and between JSB+ and JSB- ones (30.9% v 71.1% and 35.4% v 93.1%, respectively, P < .001). Of the 21 C219+ patients who had yielded a first CR, 19 (90.4%) relapsed, compared with 28 of 64 (43.7%) C219- patients (P < .001). Of the 28 JSB1+ patients in first CR, 17 (60.7%) relapsed relative to 8 (29.6%) of 27 JSBI- ones (P = .021). A higher rate of relapses among MDR+ compared with MDR- patients was observed both for C219 and JSB1 MoAbs taken separately (C219 80% v 44%; JSB1 52% v 27%), with no relationship to age. The survival rates (Kaplan-Meyer method) were significantly shorter both in C219+ patients and in JSB1+ cases (P < .001). Disease-free survival curves followed this same trend. The combination (C219- JSB1+) identified a subset of patients with an intermediate outcome compared to C219 positive cases. The prognostic value of both markers (C219 and JSB1) was confirmed in multivariate analysis. These results suggest that the assessment of MDR phenotype by flow cytometry may be an important predictor of treatment outcome.

Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution's experience

Blood ◽  
2001 ◽  
Vol 97 (12) ◽  
pp. 3727-3732 ◽  
Author(s):  
Uma H. Athale ◽  
Bassem I. Razzouk ◽  
Susana C. Raimondi ◽  
Xin Tong ◽  
Frederick G. Behm ◽  
...  
Keyword(s):  
Down Syndrome ◽  
De Novo ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Transplantation ◽  
Remission Induction ◽  
Allogeneic Bone ◽  
Acute Megakaryoblastic Leukemia ◽  
Free Survival ◽  
Megakaryoblastic Leukemia ◽  
De Novo Aml

To describe the clinical and biologic features of pediatric acute megakaryoblastic leukemia (AMKL) and to identify prognostic factors, experience at St Jude Children's Research Hospital was reviewed. Of 281 patients with acute myeloid leukemia treated over a 14-year period, 41 (14.6%) had a diagnosis of AMKL. Six patients had Down syndrome and AMKL, 6 had secondary AMKL, and 29 had de novo AMKL. The median age of the 22 boys and 19 girls was 23.9 months (range, 6.7-208.9 months). The rate of remission induction was 60.5%, with a 48% rate of subsequent relapse. Patients with Down syndrome had a significantly higher 2-year event-free survival (EFS) estimate (83%) than did other patients with de novo AMKL (14%) or with secondary AMKL (20%;P ≤ .038). Among patients who had de novo AMKL without Down syndrome, 2-year EFS was significantly higher after allogeneic bone marrow transplantation (26%) than after chemotherapy alone (0%;P = .019) and significantly higher when performed during remission (46%) than when performed during persistent disease (0%;P = .019). The 5-year survival estimates were significantly lower for de novo AMKL (10%) than for other forms of de novo AML (42%; P &lt; .001). Treatment outcome is very poor for patients with AMKL in the absence of Down syndrome. Remission induction is the most important prognostic factor. Allogeneic transplantation during remission offers the best chance of cure; in the absence of remission, transplantation offers no advantage over chemotherapy alone.

Gene Expression Profile of Acute Myeloid Leukemia (AML) with t(8;16)(p11;p13) and MYST3/CREBBP Rearrangement.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2054-2054
Author(s):  
Mireia Camos ◽  
Jordi Esteve ◽  
Pedro Jares ◽  
Maria Rozman ◽  
Dolors Colomer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
De Novo ◽  
Normal Karyotype ◽  
Genetic Profile ◽  
Transferase Activity ◽  
Internal Tandem Duplication ◽  
Its Gene ◽  
Differential Expression Profile

Abstract Translocation t(8;16)(p11;p13) is an infrequent chromosomal abnormality in de novo and secondary AML cases, leading to the fusion of MYST3 (MOZ) and CREBBP (CBP) genes, both of them harboring histone lysine acetyl-transferase activity. This AML variety displays specific clinical and biological features, although its gene expression profile is currently unknown. In this study, the genetic signature of AML cases with MYST3/CREBBP rearrangement was compared with the genetic profile of other well-defined AML subtypes. Genotypic analyses using oligonucleotide U133A arrays (Affymetrix) were performed on RNA of 19 AML samples, including t(8;16)-AML (n=3), t(15;17) (n=3), t(8;21) (n=2), inv(16)/t(16;16) (n=3), t(9;11) with AF9/MLL rearrangement (n=2), 3 cases with normal karyotype and flt-3 internal tandem duplication (flt-3 ITD), the three remaining samples corresponding to monocytic cases (M4/M5) without MLL rearrangement nor flt-3 ITD. After unsupervised analysis, cases of AML with t(8;16) clustered together, displaying a differential expression profile. Supervised analysis allowed the identification of the top 53 up-regulated and 28 down-regulated genes. Among the set of genes overexpressed, genes involved in chromatin remodelling and transcription (HOXA9, HOXA10, MEIS1, CHD3, SATB1) and protooncogenes (RET, flt-3, LMO2) were identified. In contrast, CREBBP gene and several members of the JAK-STAT pathway (STAT3, STAT5B, JAK2) were underexpressed. Interestingly, overexpression of multiple homeobox genes was detected in flt-3 ITD cases, some of them as a distinctive finding (HOXA2, HOXA3, HOXB6), and others (HOXA9, HOXA10, MEIS1) were found to be highly expressed in MYST3/CREBBP and MLL-rearranged samples. In conclusion, AML with t(8;16) and MYST3/CREBBP rearrangement shows a distinctive gene expression profile, with some similarities with MLL rearranged leukemias and flt-3 ITD AML cases, thus suggesting a partially common leukemogenic pathway.

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