scholarly journals Molecular associations, clinical, and prognostic implications of PTPN11 mutations in acute myeloid leukemia (Alliance)

2021 ◽  
Author(s):  
Sydney Fobare ◽  
Jessica Kohlschmidt ◽  
Hatice Gulcin Ozer ◽  
Krzysztof Mrózek ◽  
Deedra Nicolet ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Tyrosine Phosphatase ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Early Death ◽  
Sh2 Domain ◽  
Phosphatase Domain ◽  
Molecular Group ◽  
Acute Myeloid

Prognostic factors associated with chemotherapy outcomes in patients with acute myeloid leukemia (AML) are extensively reported, and one gene whose mutation is recognized as conferring resistance to several newer targeted therapies is protein tyrosine phosphatase non-receptor type 11 (PTPN11). The broader clinical implications of PTPN11 mutations in AML are still not well understood. The objective of this study was to determine which cytogenetic abnormalities and gene mutations co-occur with PTPN11 mutations and how PTPN11 mutations impact outcomes of patients treated with intensive chemotherapy. We studied 1,725 newly diagnosed AML patients (excluding acute promyelocytic leukemia) enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. In 140 PTPN11-mutated patient samples, PTPN11 most commonly co-occurred with mutations in NPM1, DNMT3A, and TET2. PTPN11 mutations were relatively common in patients with an inv(3)(q21q26)/t(3;3)(q21;q26) and a normal karyotype but were very rare in patients with typical complex karyotype and core-binding factor AML. Mutations in the N-terminal SH2 domain of PTPN11 were associated with a higher early death rate than those in the phosphatase domain. PTPN11 mutations did not affect outcomes of NPM1-mutated patients, but these patients were less likely to have co-occurring kinase mutations (i.e., FLT3-ITD), suggesting activation of overlapping signaling pathways. However, in AML patients with wild-type NPM1, PTPN11 mutations were associated with adverse patient outcomes providing a rationale to study the biology and treatment approaches in this molecular group.

Clinical usefulness of plasma specimens for detection of nucleophosmin 1 gene mutations in patients with normal karyotype acute myeloid leukemia

2011 ◽  
Vol 35 (9) ◽  
pp. e159-e160 ◽  
Author(s):  
Sang Hyuk Park ◽  
Sook-Kyung Min ◽  
Borae G Park ◽  
Seongsoo Jang ◽  
Chan-Jeoung Park ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Clinical Usefulness ◽  
Acute Myeloid

TET2, ANPM1 and FLT3-ITD Gene Mutations in Normal Karyotype Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1413-1413
Author(s):  
Aining Sun ◽  
Xiaopeng Tian ◽  
Jia Yin ◽  
Weiyang Li ◽  
Suning Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Genetic Mutation ◽  
Wild Type ◽  
Cell Percentage ◽  
High Bone ◽  
Acute Myeloid

Abstract Abstract 1413 Objective: Analyze the molecular genetics characteristics of acute myeloid leukemia with normal karyotype and explore the relationship between different genetic mutation patterns and prognosis. Methods: A total of 373 acute myeloid leukemia (AML) with normal karyotype diagnosed and treated in the First Affiliated Hospital of Soochow University from 2005 to 2010 were recruited in this research to assess the genetic mutation patterns. The target genes which was extracted from bone marrow cell were amplified by PCR and analyzed by massively DNA sequencing. All of the TET2, DNMT3A, IDH1, IDH2, EZH2, CBL, ASXL1, MLL-PTD, NPM1, WT1, RUNX1, c-KIT, FLT3-ITD, FLT3-TKD, N-RAS and JAK2V617F gene mutations were detected in our study. Results: (1). A total of 16.1% of patients had TET2 mutations, 31.6% had FLT3 internal tandem duplications (ITDs), 6.2% had FLT3 tyrosine kinase domain mutations, 2.4% had c-KIT mutations, 37.8% had NPM1 mutations, 11.3% had WT1 mutations, 5.9% had RUNX1 mutations, 11.5% had ASXL1 mutations, 3.8% had MLL partial tandem duplications (PTDs), 7.8% had IDH1 mutations, 7.8% had NRAS mutations, 12.3% had IDH2 mutations, 1.6% had EZH2 mutations, 14.7% had DNMT3A mutations and no mutations were found of CBL and JAK2V617F. In conclusion, there are 77% (287/373) gene mutations hide in normal karyotype AML patients.(2). We found that the TET2 gene mutations were associated with DNMT3A (P = 0.041) and RUNX1 (P <0.001) mutations, but mutually exclusive with IDH2 (P = 0.021), or IDH1/2 (P = 0.006) gene mutations. NPM1 gene mutations were highly correlated with DNMT3A mutations (P <0.0001), IDH1 mutations (P <0.0001) and IDH2 mutations (P = 0.001), but mutually exclusive with RUNX1 mutations (P=0.003). IDH2 mutations and WT1 mutations were mutually exclusive (P = 0.01); DNMT3A mutations were associated with NRAS mutations (P = 0.01). In addition, study have shown that the number of gene mutations was closely associated with older age, high white blood cell and high bone marrow blast cell percentage, but wasn't correlated with gender, hemoglobin and platelet levels.(3). In the NPM1m+ patients, TET2 mutations were associated with shorter median OS in contrast to TET2 wild type (9.9 vs. 27.0 months, P= 0.023). Surprisingly, in NPM1m+/FLT3-ITDm- group, TET2 mutations was also an unfavorable prognostic factor, which was closely associated with shorter median OS compared to TET2 wild type (9.5 vs. 32.2 months, P=0.013). Conclusion: Gene mutations incidence was high in normal karyotype AML patients. TET2 mutations was an unfavorable prognostic factor which was closely associated with shorter median OS in contrast to TET2 wild type in NPM1m+/FLT3-ITDm-group. In addition, The number of gene mutation was closely associated with older age, high white blood cell levels and high bone marrow blast cell percentage. Disclosures: No relevant conflicts of interest to declare.

Chromosome Aberrations, Gene Mutations and Expression Changes, and Prognosis in Adult Acute Myeloid Leukemia

Hematology ◽  
2006 ◽  
Vol 2006 (1) ◽  
pp. 169-177 ◽  
Author(s):  
Krzysztof Mrózek ◽  
Clara D. Bloomfield
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Chromosome Aberrations ◽  
Myeloid Leukemia ◽  
Molecular Genetic ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Genetic Alterations ◽  
Acute Myeloid

Abstract Pretreatment clinical features and prognosis of patients with acute myeloid leukemia (AML) are strongly influenced by acquired genetic alterations in leukemic cells, which include microscopically detectable chromosome aberrations and, increasingly, submicroscopic gene mutations and changes in gene expression. Cytogenetic findings separate AML patients into three broad prognostic categories: favorable, intermediate and adverse. The cytogenetic-risk classifications differ somewhat for younger adult patients and those aged 60 years or older. In many instances, patients with specific cytogenetic findings, e.g., those with a normal karyotype or those with either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) [collectively referred to as core-binding factor (CBF) AML] can be further subdivided into prognostic categories based on the presence or absence of particular gene mutations or changes in gene expression. Importantly, many of these molecular genetic alterations constitute potential targets for risk-adapted therapies. In this article, we briefly review major cytogenetic prognostic categories and discuss molecular genetic findings of prognostic significance in two of the largest cytogenetic groups of patients with AML, namely AML with a normal karyotype and CBF AML.

Analysis of NPM1 Gene Mutations in Chinese Adults with Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4503-4503
Author(s):  
De Pei Wu ◽  
Lingzhi Yan ◽  
Suning Chen ◽  
Jianying Liang ◽  
Yufeng Feng
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Chinese Patients ◽  
Chinese Adults ◽  
Cytoplasmic Transport ◽  
Acute Myeloid

Abstract Many European groups have described that mutations at exon-12 of the nucleophosmin (NPM1) gene are the most frequent genetic lesion in acute myeloid leukemia (AML) (45.7%~61.7% of all adult AMLs with normal karyotype). This outstanding discovery provides a promising minimal residual disease (MRD) marker for AMLs with normal karyotype. To clarify the prevalence and the clinical profile of NPM1 mutations in Chinese patients with AML, we analyzed a cohort of 156 newly diagnosed adult AMLs for this mutation. Genomic DNAs were prepared from bone marrow samples of these patients. NPM1 exon 12 mutations were detected using direct sequencing or fragment analysis of DNA-PCR products. NPM1 mutations were present in 28.2% of the overall population, including 1/1(100%) of M0, 11/27(40.7%) of M1, 11/46(23.9%) of M2, 0/29(0%) of M3, 2/9(22.2%) of M4, 18/39(46.2%) of M5 and 1/5(20.0%) of M6. NPM1 gene mutations were more prevalent in patients with a normal karyotype (37 of 90; 41.1%), when compared with patients with karyotypic abnormalities (7 of 66; 10.6%; P&lt;0.001). Sequence analysis of 25 NPM1 mutated cases revealed known mutations (type A, B, NM, and PM) as well as 1 novel sequence variation (here named as type S). All mutational types were heterozygous and showed a 4 bp insertion between position nucleotide 960 and 961 (Genebank accession number: NM-002500). NPM1 mutations were significantly associated with old age (P&lt;0.05), high peripheral white cell count (P&lt;0.05) and FAB-M1/M5, but negatively associated with expression of CD34 (P&lt;0.05) and CD117 (P&lt;0.05). In conclusion, NPM1 mutations also represent a common genetic abnormality in Chinese adults with AML, especially in the presence of a normal karyotype. The occurrence of NPM1 mutations indicates an age-dependent characteristic. NPM1 mutated cases show a special clinical subtype of AML. Further studies are urgently needed to confirm the role of NPM1 mutations in leukemogenesis. The altered nucleo-cytoplasmic transport of NPM1 mutated protein is probably a potential therapic target for AML with NPM1 mutations.

Characterization of Acute Myeloid Leukemia with PTPN11 Mutation - The Mutation Is Closely Associated with NPM1 Mutation but Inversely Related to FLT3/ITD.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3490-3490 ◽  
Author(s):  
Hsin-An Hou ◽  
Wen-Chien Chou ◽  
Chien-Yuan Chen ◽  
Liang-In Lin ◽  
Jih-Luh Tang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Tyrosine Phosphatase ◽  
Normal Karyotype ◽  
Receptor Protein ◽  
Missense Mutations ◽  
Npm1 Mutation ◽  
Ptpn11 Mutation ◽  
Acute Myeloid

Abstract The development of acute myeloid leukemia (AML) is a multistep process. Recently, somatic mutations of PTPN11, the gene encoding non-receptor protein tyrosine phosphatase SHP-2, were observed in some hematological malignancies. However, the characteristics of adult AML with PTPN11 mutations have not been comprehensively studied, and the specific genetic alteration cooperative with a PTPN11 mutation in the leukemogenesis remains largely unknown. In this study, PTPN11 mutation and its association with other gene aberrations were analysed for 272 adult patients with de novo AML. Missense mutations were identified in 14 individuals (5.1%). The PTPN11 mutation was closely associated with old age (P=0.036), FAB M4/M5 subtypes (P=0.049), CD14 expression (P=0.026), a normal karyotype (P=0.044) and NPM1 mutation (P=0.037), but negatively associated with FLT3/ITD (P = 0.025). In addition, four patients revealed simultaneous mutations of PTPN11 and AML1 (n=3) or MLL (n=1). We observed a shorter overall survival for patients with PTPN11 mutation than those without amongst NPM1-wild patients (P=0.001), but not amongst NPM1-mutated patients (P=0.738). Our findings provide evidence that AML patients with PTPN11 mutations had some distinct biological and clinical characteristics, and the mutation may cooperate with other gene alterations to lead to AML in a subset of patients.

Nucleophosmin Gene Mutations Exhibit High Spontaneous Apoptosis and Favorable Prognosis in Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3480-3480
Author(s):  
Giovanni Del Poeta ◽  
Emanuele Ammatuna ◽  
Serena Zaza ◽  
Francesco Buccisano ◽  
Tiziana Ottone ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Proliferative Potential ◽  
Spontaneous Apoptosis ◽  
Favorable Prognosis ◽  
Acute Myeloid

Abstract Nucleophosmin gene mutations (NPM1-Mt) are the hallmark of a large adult acute myeloid leukemia (AML) subgroup with normal karyotype and interact with p53 and its regulatory molecules (Arf, Hdm2/Mdm2), thus lowering cell proliferation and increasing apoptosis (Falini, 2007). Moreover, AML pts show co-existing NPM1-Mt and internal tandem duplications of FLT3 (FLT3-ITD) which increase potential for cell proliferation. Furthermore, genes and proteins involved in apoptosis, such as bcl-2 and bax, have been demonstrated to be relevant in response to treatment and outcome (Del Poeta, 2003). Therefore, we analysed NPM1-Mt, FLT3-ITD and apoptosis proteins (bcl-2 and bax) in 222 pts, affected by de novo non-M3 AML, median age 60 years, treated with intensive chemotherapy regimens according to GIMEMA-EORTC protocols. The aims of our study were: to correlate NPM1-Mt or FLT3-ITD with bax/bcl-2 ratio levels, as a measure of spontaneous apoptosis; to assess the independent prognostic significance of NPM1-Mt and FLT3-ITD. Bcl-2 and bax proteins were determined by multicolor flow cytometry and bax/bcl-2 ratio was obtained by dividing mean fluorescence intensity (MFI) of bax/MFI bcl-2. The threshold of positivity was set at the median value >0.35 (range 0.01–9.1). NPM1 mutations and FLT3-ITD were detected by multiplex PCR and capillary gel electrophoresis. One hundred-twenty-one/222 (54.5%) pts were bax/bcl-2 ratio positive, 54/222 (24.3%) were NPM1-Mt and 52/222 (23.4%) presented FLT3-ITD; 17/222 (7.6%) pts carried both FLT3-ITD and NPM1-Mt. There was a strong correlation between higher WBC counts (>100x109/L) and FLT3-ITD (P<0.00001), confirming their high proliferative potential. On the contrary, a higher apoptosis (bax/bcl-2 ratio>0.35) and NPM1-Mt without FLT3-ITD were significantly associated (30/37; P=0.0001), demonstrating that NPM1-Mt alone express high amount of spontaneous apoptosis. Moreover, NPM1-Mt cases were significantly related to FAB M4 or M5 AML (P=0.03). A normal karyotype was found in 37/45 (82%) NPM1-Mt pts (P=0.00001) and almost all NPM1-Mt cases were CD34 negative (47/54; P<0.00001). With regard to clinical outcome, a significant higher complete remission (CR) rate was found in NPM1-Mt/FLT3-ITD negative pts (90%) vs NPM1-Mt/FLT3-ITD+ (35%) or only FLT3-ITD+ cases (47%) [P=0.0002]. Equally, overall survival (OS) was significantly longer in NPM1-Mt/FLT3-ITD negative pts in comparison with NPM1-Mt/FLT3-ITD+ or only FLT3-ITD+ cases (35% vs 0% vs 6% at 2 years; P=0.00007). Furthermore, NPM1-Mt/FLT3-ITD negative subset showed a disease free survival longer than only FLT3-ITD+ cases (44% vs 0% at 1.2 years; P=0.008). Finally, NPM1-Mt/FLT3-ITD negative pts showed a better outcome than the large subgroup negative both for NPM1-Mt and FLT3-ITD, with regard to CR (90% vs 66%) and OS (35% vs 15% at 2 years). In multivariate analysis, bax/bcl-2 ratio (P<0.00001), age (P=0.0003) and FLT3-ITD (P=0.01) were significant for CR, while bax/bcl-2 ratio (P<0.00001), WBC count (P=0.01) and FLT3-ITD (P=0.01) resulted to be independent prognostic factors for OS. In conclusion, we demonstrated that NPM1 mutations exhibit high levels of spontaneous apoptosis, which strenghten, in the absence of FLT3-ITD, their favorable prognosis. On the contrary, FLT3-ITD dominate the myeloid leukemic phenotype conferring a poor outcome to pts with NPM1 mutations.

Nucleophosmin Gene Mutations Identify a Favorable Risk Group in Childhood Acute Myeloid Leukemia with a Normal Karyotype.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 366-366
Author(s):  
Iris H. Hollink ◽  
Christian M. Zwaan ◽  
Marry M. van den Heuvel-Eibrink ◽  
Martin Zimmerman ◽  
Susan Arentsen-Peters ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Type A ◽  
Prognostic Impact ◽  
Wild Type ◽  
Molecular Abnormalities ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Exon 12 gene mutations in nucleophosmin (NPM1) were recently discovered in approximately 30% of adult acute myeloid leukemia (AML) samples, and cluster in the normal karyotype subgroup (NK-AML). NPM1-mutated adult NK-AML has a favorable outcome (pOS in the 40-50% range), but in case a FLT3 internal tandem duplication (FLT3/ITD) is also present outcome is worse with 25–30% pOS. In pediatric AML, NPM1 mutations are less frequent (6–8%; Cazzaniga, Blood 2005 & Brown, Blood 2007). No studies have specifically addressed pediatric NK-AML, a subgroup lacking favorable prognostic cytogenetic aberrations and therefore mostly stratified in the intermediate risk arm of pediatric AML treatment protocols. We screened 292 newly diagnosed AML samples, and detected NPM1 mutations in 25 cases (8.6%). We also screened 46 initial diagnosis-relapse pairs, and no clonal instability was observed, which suggests that NPM1 mutations may be used for minimal residual disease detection. In contrast to adults, where type A mutations (TCTG-insertion) are most frequent (80%), in our cohort type B (CATG-insertion) mutations were found in 39% and type A in 23%. In the NK-AML cohort (n=98), 20% was NPM1-mutated, which was age dependent: &lt;3 years, 0%; 3–10 years, 19%; &gt;10 years, 29% (p=0.04). None of the 10 FAB M5 cases was NPM1 mutated (p=0.09). NPM1 mutations had an independent favorable prognostic impact on outcome in patients with NK-AML (5-year pEFS 77% vs. 41% for wild type patients; p=0.003), irrespective of FLT3 mutational status. In fact, NPM1-mutated patients with a FLT3/ITD did better than patients without an ITD, although this was not statistically significant (5-year pEFS 90% vs. 63%, respectively; p=0.48). In NK-AML without NPM1 mutations, patients with FLT3/ITD positive AML did significantly worse than wild type FLT3 AML patients (5-year pEFS 18% vs. 52%, p=0.002). The differential prognostic impact of FLT3/ITD between the NPM1-mutated vs. the wild type patients was not caused by differences in the FLT3/ITD allelic ratio or ITD length, nor was there a relationship with the type of NPM1 mutations. Multivariate analysis, including age, white blood cell count, NPM1 and FLT3 status and stem cell transplantation as time-dependent co-variable, showed that only NPM1 mutations had independent prognostic significance for pEFS (RR 0.34, p=0.02). We conclude that the incidence of NPM1 mutations increases with age, and that NPM1 mutations define a subgroup with favorable prognosis in pediatric NK-AML. Our data suggest that these molecular abnormalities allow stratification of children with NK-AML. However, different from adult NK-AML, we observed that all children with NPM1 mutations did well, irrespective of FLT3 status. Therefore, treatment in the ‘good risk’ arm should be considered for children with NPM1-mutated NK-AML.

The Analysis of FLT3 and NPM1 Gene Mutations in Chinese Patients with Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4136-4136
Author(s):  
Su-Jiang Zhang ◽  
Jianyong Li ◽  
Yangli Han
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Leukemia Cell ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Chinese Patients ◽  
Npm1 Mutation ◽  
Double Mutation ◽  
Acute Myeloid

Abstract Abstract 4136 Objective To investigate the frequency of nucleophosmin(NPM1) gene mutations and FLT3 mutations in Chinese patients with acute myeloid leukemia (AML) and its correlation with clinical feature and prognosis. Methods 123 first diagnosed AML patients were involved in our study. Polymerase chain reaction (PCR) combined with electrophoresis was directly used to detect FLT3-ITD mutations, PCR combined with EcoRV digestion was used to detect FLT3-TKD mutation, and PCR combined with directly sequencing was used to detect NPM1 mutations. Results (1) In the 123 first diagnosed AML patients, 16 patients (13.0%) were found harboring FLT3-ITD mutation, 6 patients (4.9%) were FLT3-TKD positive, and one patient was found harboring co-existing FLT3-ITD and FLT3-TKD mutation. In addition, 24 patients (19.8%) were NPM1 positive, including 22 patients with A-type mutation, one patient with B-type mutation and one patient with D-type mutation. 5 patients were found harboring co-existing FLT3-ITD and NPM1 mutation. (2) FLT3-ITD and NPM1 mutations were identified as 17.5% (10/57) and 31.6% (18/57) individually in 57 AML patients with normal karyotype, which were significantly higher than patients with abnormal karyotype. All of patients with double mutation had normal karyotype. (3) White blood cell (WBC) count and leukemia cell of bone marrow in FLT3-ITD or FLT3-ITD+/NPM1+ patients were both higher than those patients with FLT3-ITD-/NPM1-. The CR rate of FLT3-ITD+/NPM1-, FLT3-ITD+/NPM1+, FLT3-ITD-/NPM1+, FLT3-ITD-/NPM1- were 50% (4/8), 20% (1/5), 87.5% (7/8), 79.5% (35/44) individually. Conclusions FLT3 gene and NPM1 gene mutations are common in AML patients, and early detection of FLT3 gene and NPM1 gene mutations will be beneficial for treatment and prognosis analysis of AML patients. Disclosures: No relevant conflicts of interest to declare.

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