Analysis of Clonal Cytogenetic Abnormalities in 143 Patients with Secondary AML/MDS

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1473-1473
Author(s):  
Elena V Domracheva ◽  
Elena A Aseeva ◽  
Galina A Alimova ◽  
Olga S Kremenetskaya ◽  
Liubov A Shishigina ◽  
...  
Keyword(s):  
Bone Marrow ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Chromosome 7 ◽  
Secondary Neoplasms ◽  
Monosomy 7 ◽  
Cytogenetic Abnormalities ◽  
De Novo Aml ◽  
Secondary Mds ◽  
Balanced Translocations

Abstract Abstract 1473 The incidence of the secondary neoplasms has increased because of the rising numbers of long-term survivors of tumours. Secondary leukemias (sL) and secondary MDS (sMDS) are among the most common types of secondary tumours. Until recently prognosis in cases of sL and sMDS was considered less favorable than in leukemias de novo. Age at presentation and identified clonal cytogenetic abnormalities are among the most important independent prognostic factors in adult patients with leukemias. It is obvious today that the presence of t(15;17)(q22;q12), t(8;21)(q22;q22), inv(16)(p13;q22)/t(16,16)(p13;q22) predicts a relatively favorable outcome, and in contrast the presence of inv(3)(q21q26)/t(3,3)(q21;q26), del(5q), −5, −7 or a complex karyotype (CK) with 3 or more abnormalities generally suggests a very poor prognosis. The monosomal karyotype (MK) defined as two or more distinct autosomal chromosome monosomies or one single autosomal monosomy in combination with at least one structural chromosomal abnormality is also considered as an adverse prognostic factor according to Breems D.A. et al., 2008; Medeiros B.C. et al., 2010 4-year overall survival in AML patients with MK is very low – 3–4%. Therefore, the purpose of our analysis was to determine the frequency of “unfavorable” and “highly unfavorable” (according to Breems D.A. et al.) clonal cytogenetic abnormalities, identified in our laboratory in bone marrow samples of 143 patients with sL/sMDS and to compare it with the frequency of MK in leukemias and MDS de novo according to a published multicenter study (Haase D. et al., 2007; Medeiros B.C. et al., 2010; Grimwade D. et al., 2010). All examined patients with sL/sMDS had solid tumors or lymphomas in anamnesis, for which they received chemotherapy and/or radiotherapy. sMDS was identified in 81 patients (54 patients – ≤5% blasts in bone marrow; in 27 patients – >5%). sAML was identified in 56 patients, sALL – in 1 patient, sCML – in 5 patients. Abnormal karyotypes were observed in 42 (52%) sMDS patients, in 37 (66%) sAML patients, in all 5 sCML patients, in the only sALL patient. The most frequent abnormality in sMDS was isolated monosomy 7: it was observed in 24.4% of the tested abnormal karyotypes. CK and MK are considerably more frequent in sMDS than in de novo MDS. CK occurred in 12 (30.9%) sMDS patients with abnormal karyotypes. Monosomies or deletions of the long arm of chromosome 7 were detected in 8 of 12 identified CK. Balanced translocations in sMDS were detected in only 9 (21%) of 42 karyotypes; no rearrangements involving 3q26, rather frequently occurred in de novo MDS, were registered. Very rare for de novo MDS t(1;7)(q10;q10) was found in 5 of these 9 cases. In general, chromosome 7 abnormalities (translocations, monosomies and/or deletions) were observed in 58.5% of sMDS cases with abnormal karyotypes. In de novo MDS chromosome 7 abnormalities were detected only in 21% of cases. On the contrary, del(5q) occurred more frequently in de novo MDS than in sMDS (30% versus 12.2%). Monosomic karyotypes occurred in 23.8% of sMDS patients with abnormal karyotypes. “Favorable” anomalies were presented in 5 of 37 sAML cases (13,5%) abnormal karyotypes. t(15;17), as a single anomaly, was detected in 3 patients; t(8;21) was detected in 2 cases. “Unfavorable” abnormalities, such as inv(3)(q21;q26)/t(3;3)(q21;q26) in complex karyotypes were observed in 4 cases. Chromosome 5 deletions in complex karyotypes were found in 5 cases, and only in 1 case - as a single anomaly. Other deletions, del(11)(q23), del(12)(p11), del(13)(q12), were found only as isolated anomalies. Complex karyotypes in sAML were observed in 40% (15 of 37) of cases with abnormal karyotypes, whereas in de novo AML CK occurred only in 18% of patients with abnormal karyotypes. Monosomic karyotypes occurred more often in patients with sAML - 27% compared to 13% of cases in de novo AML. In conclusion, prognostically “unfavorable” and “highly unfavorable” cytogenetic abnormalities account for 60% and 25% of all cases with karyotype abnormalities in sAML/sMDS. Thus, our study shows that “unfavorable” and “highly unfavorable” cytogenetic abnormalities in leukemic clone occur more often in sAML/sMDS than in de novo AML/MDS. Disclosures: No relevant conflicts of interest to declare.

Significance of Bone Marrow Karyotype and Morphology in Patients with Inherited Bone Marrow Failure Syndromes,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3431-3431
Author(s):  
Neelam Giri ◽  
Blanche P Alter ◽  
Helkha Peredo-Pinto ◽  
M. Tarek Elghetany ◽  
Irina Maric ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Myelogenous Leukemia ◽  
Monosomy 7 ◽  
Cytogenetic Abnormalities ◽  
Bone Marrow Failure Syndromes ◽  
Number Of Patients

Abstract Abstract 3431 Recurring clonal cytogenetic abnormalities have been described in patients with Fanconi anemia (FA) and Shwachman-Diamond syndrome (SDS). In FA, gains of 3q and monosomy 7 (−7) imply progression to myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). In SDS, isochromosome 7q and deletion (del) 20q are usually benign. Dyskeratosis congenita (DC) and Diamond-Blackfan anemia (DBA) do not have unique clones. We report here the types and frequencies of cytogenetic clones and their association with morphologic MDS or AML in the major inherited bone marrow failure syndromes (IBMFS), in a prospective/ retrospective study of patients with FA, SDS, DC and DBA enrolled in the NCI IBMFS cohort from 2002–2010. Bone marrow (BM) morphology and cytogenetics (G-banding; selected FISH, CGH, SKY) performed at our institute and all outside cytogenetics reports were centrally reviewed. Cytogenetic abnormalities were defined and karyotypes designated according to ISCN (2009). Two independent blinded hematopathologists reviewed BM morphology. Diagnosis of morphologic MDS was based on a modification of WHO 2008 and required ≥10% dysplasia in 2 cell lineages. Data analysis was both cross-sectional and longitudinal. P values are global comparing all 4 disorders using Fisher's exact test.ParameterAll IBMFSFASDSDCDBAP valueTotal number (N)12835113646–N with clone ever2817 (49%)4 (36%)4 (11%)3 (7%)<0.01N with MDS ever105 (14%)3 (27%)1 (3%)1 (2%)0.01N with clone + MDS75 (14%)2 (18%)00<0.01N with clone alone2112 (34%)2 (18%)4 (11%)3 (7%)<0.01N with MDS alone301 (9%)1 (3%)1 (2%)0.3N with clone at 1st BM179 (26%)4 (36%)3 (8%)1 (2%)<0.01N with clones at follow-up118012<0.01N with follow-up BMs591791716–Median follow-up in years3 (0–19)6 (1–16)2 (1–6)3 (0–19)2 (0–10)– More FA and SDS patients had clones and/or MDS compared with DC or DBA (Table). MDS was always associated with clones in FA but not in the other IBMFS. In FA, bone marrow transplant (BMT) or death occurred with similar frequencies in those with or without clones. Among 17 patients with clones, follow-up cytogenetics were unavailable in 5; of these, 2 with clone alone [one with del 7q and 18p and one with t(3;6)(q?25;p?21)] progressed to AML, while one with clone and MDS died from other causes. Recurring abnormalities in 12 FA patients with clones followed for up to 16 years, included gains of 1q in 4, −7 or del 7q in 3, and deletions of 6p, 13q, 18p and 20q in 2 patients each; only one had gain of 3q. These patients showed fluctuation or disappearance of clones, new appearance of clones, stable clone, or clonal evolution. Progression to MDS occurred with gain of 1q and 6p deletion, gain of 3q, or −7 in 3 patients, respectively; one patient with MDS had clonal persistence. No disease progression was seen in 5 FA patients with clone alone. All 5 SDS patients with clones and/or MDS are alive with no disease progression. The 4 with a clone had stable persistent del 20q as a sole abnormality; 2 had MDS and 2 did not. One had MDS with a normal karyotype. Four DC patients had abnormal clones including 2 with gain of 1q only. One patient with 1q gain died from pulmonary fibrosis. Three others are alive; 2 with stable clones at 7 and 19 years' follow-up, respectively. One additional DC patient has morphologic MDS but no clone. All 3 DBA patients with clones had del 16q, 2 alone and 1 with del 9p; none had MDS. The clones were transient in 2, disappearing within 1–2 years; the third was recently identified. None of these had disease progression. One patient with morphologic MDS alone died from complications of iron overload. This study shows that clonal chromosome abnormalities occur more frequently in FA and SDS than in DC and DBA. Gain of 3q in FA was not as common here as reported by others. This is the first comprehensive study of clones and MDS in DC and DBA. Strengths of this study include the large number of patients, and central review of cytogenetics and morphology. It is unbiased compared with FA literature reports that include many patients referred for BMT. Limitations include a relatively small number of patients with each diagnosis and short follow-up in most. The study demonstrates that clones may fluctuate or disappear, and may not per se portend a bad prognosis. Progression to clinically significant MDS or AML may be related to the severity of cytopenias and not to clone alone, and warrants more extensive long-term studies. Disclosures: No relevant conflicts of interest to declare.

IDH1/2, TET2 and DNMT3A Mutations Are Not Mutually Exclusive in Secondary Acute Myeloid Leukemias,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3556-3556
Author(s):  
Olivier Kosmider ◽  
Olivier LaRochelle ◽  
Marie-Magdelaine Coude ◽  
Veronique Mansat-De Mas ◽  
Eric Delabesse ◽  
...  
Keyword(s):  
Bone Marrow ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Remission Rate ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Myeloid Leukemias ◽  
Melting Analysis ◽  
De Novo Aml

Abstract Abstract 3556 IDH1/2, TET2 and DNMT3A mutations have been reported in myeloid malignancies including de novo AML. In this study, we have analyzed the frequency and prognostic impact of these mutations in a large retrospective cohort of patients (pts) with secondary AML (SA) which encompass myelodysplasia-related changes (MRC) AML and therapy-related (TR) AML according to the WHO classification. Bone marrow samples were collected from 247 pts at diagnosis with SA and the mutational status of IDH1/2, TET2 and DNMT3A genes together with other genes frequently mutated in AML (NPM1, FLT-3, N and K-RAS, WT1) was determined by Sanger sequencing or high resolution melting analysis. The cohort of 247 pts consisted in 201 MRC AML and in 46 TR AML, 39.5% of which with a normal karyotype (NK). The frequency of IDH1/2, TET2 and DNMT3A mutations was 12.6, 19.8 and 4.5%, respectively. Two pts had both TET2 and IDH1/2 mutations, 2 pts had TET2 and DNMT3A mutations and 5 pts had both IDH1/2 and DNMT3A mutations showing that these mutations were not mutually exclusive in SA. IDH1/2 and TET2 mutations were significantly more frequent in MRC AML (14.1 and 22.3%) than in TR AML (6.4 and 8.7%) (P =0.04 and P =0.03) while the frequency of DNMT3A mutations was identical in the two subgroups. The SA pts harbouring at least one IDH1/2 or TET2 or DNMT3A mutation were significantly older (P <0.0001) and presented higher leukocyte count and lower MCV (P <0.05) than unmutated pts. Percentage of blasts in the bone marrow was similar in the two groups. Karyotype was normal in 48% of the IDH1/2 or TET2 or DNMT3A mutated pts and 18% of the unmutated patients, indicating that these mutations were strongly associated with NK (P < 0.001). A statistically significant link was found between TET2 or IDH1/2 or DNMT3A mutations and NPM1 mutations, but not with FLT-3, N/K-RAS or WT1 mutations. Complete remission rate and overall survival were evaluated in a group of 158 pts which had received intensive chemotherapy at diagnosis, and were identical in the IDH1/2 or TET2 or DNMT3A mutated and unmutated groups. These mutations did significantly influence survival neither in the subgroup of pts with normal karyotype, nor in the subgroup of MRC-AML, or TR-AML which were of very poor prognosis. These data show that IDH1/2, TET2 or DNMT3A mutations could modify the clinical presentation without impact on prognosis. Disclosures: No relevant conflicts of interest to declare.

Time Course of Acquisition of a CSF3R Mutation and Subsequent Development of AML in a Patient with Cyclic Neutropenia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 885-885
Author(s):  
Maksim Klimiankou ◽  
Olga Klimenkova ◽  
Lothar Kanz ◽  
Cornelia Zeidler ◽  
Karl Welte ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Allele Frequency ◽  
Critical Region ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Subsequent Development ◽  
Parental Origin ◽  
Cyclic Neutropenia ◽  
Monosomy 7

Acquired CSF3R (colony stimulating factor 3 receptor, granulocyte) mutations have been detected with a high frequency (17-34%) in severe congenital neutropenia (CN) patients. Moreover, in CN patients who developed overt acute myeloid leukemia (AML) the frequency of CSF3R mutations in the intracellular critical region reaches more than 80%. Up to now there was no report on the detection of acquired mutations in CSF3R or development of AML/MDS in cyclic neutropenia patients (CyN). This group of patients reveals the same genotype with mutations in the ELANE gene as CN patients. In contrast, both groups of patients have a clearly distinct disease penetration. Using ultra-deep sequencing approach we screened 22 CyN patients for the presence of genetic abnormalities in the critical region of the CSF3R gene. Interestingly, we found only in one CyN patient a clone with acquired mutation in G-CSF receptor (NP_000751.3, p.Gln741X) at 3% of allele frequency. The cycling neutrophils and platelets were well documented and verified the diagnosis of CyN. Within two years after the first detection, the mutant clone harboring the CSF3R mutation expanded and was detected in 16% of patient's bone marrow (BM) MNCs. The sequencing of the ELANE gene in the CyN patient with CSF3R mutation revealed the presence of two mutations p.Ala233Pro and p.Val235TrpfsX (NP_001963.1). Intriguingly, both ELANE mutations were absent in DNA isolated from each of parents indicating their de novo origin. Additionally, the patient was found to be heterozygous for synonymous SNP rs17216649 (dbSNP build 138) on the same ELANE exon permitting determination of the parental origin of mutations. The sub-clone analysis in E.coli showed that both mutations were always found on the paternally-derived allele. The missense mutation p.Ala233Pro (NP_001963.1) is well known to be associated with CN phenotype, whereas the single-base deletion p.Val235TrpfsX (NP_001963.1) was reported as cause of CN only once. There are no reports about detection of these mutations in CyN patients. Three years after the first detection of the CSF3R mutation the patient presented with 14% blast cells in bone marrow acquiring monosomy 7 and trisomy 21. Based on results of cDNA sequencing all CSF3R expressing cells in the sample were positive for p.Gln741X (NP_000751.3) mutation. Recently, we demonstrated acquisition of cooperative of RUNX1 and CSF3R mutations in more than 60% of CN-AML/MDS patients. We also found RUNX1 mutation p.Asp171Asn (NP_001001890.1) at 10% allele frequency in BM MNCs of CyN-AML patient. To evaluate at which stage of hematopoietic differentiation acquisition of CSF3R mutations appeared leading to the leukemogenic transformation, we performed colony forming unit (CFU) assays using patients BM MNCs. We observed the appearance of abnormal «CFU-blast» colonies after cultivation of BM MNCs in MethoCult H4434 Enriched medium supplemented with rh SCF, rh G-CSF, rh IL-3, rh IL-6 and rh EPO (72,2% of CFU-blasts (n=232), 21,8% of CFU-G (n=70), 5% of CFU-GM (n=16) and 1% of BFU-E (n=3)). Interestingly, we found that all sequenced CFU-G (n=4), CFU-GM (n=6) and «CFU-blast» colonies (n=20) were positive for p.Q741X CSF3R mutation. At the same time, no CSF3R mutations were identified in BFU-E colonies. In summary, we report a first case of acquisition of CSF3R mutation and subsequent development of AML in a CyN patient underlying the complex nature of genotype:phenotype relations in CN and CyN patients. This case also represents an example of an extremely rare situation of double de novo ELANE mutations and provides a unique opportunity to investigate pathogenic molecular mechanisms of leukemia development in CyN patients. The ultra-deep next generation sequencing (NGS) for identification of CSF3R mutations is a useful tool to study the frequency of CSF3R mutations not only in CN but also in CyN patients and is clinically important for the identification of patients with the risk of progression to leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Runx1 Deficiency and MDS-Associated U2af1 Mutation Cooperate for Leukemia Development in a New Mouse Model

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 964-964
Author(s):  
Tao Zhen ◽  
Dennis Liang Fei ◽  
Ling Zhao ◽  
Guadalupe Lopez ◽  
Harold Varmus ◽  
...  
Keyword(s):  
Bone Marrow ◽  
De Novo ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Genetic Alterations ◽  
Poly I:C ◽  
Cooperative Effects ◽  
Hematopoietic Malignancies ◽  
Disease Mutations ◽  
De Novo Aml

Abstract The pathogenesis of hematopoietic malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), is very complicated with mutiple genetic alterations required for full-blown disease. Mutations of splicing factor genes, including U2AF1, are found in overal half of MDS patients and 5~10% de novo AML patients. U2AF1 mutations, occuring in roughly 10% of patients with MDS and 3% in de novo AML, are heterozygous and localized almost exclusively in two codons, S34 and Q157, suggesting they are gain-of-function mutations. In addition, our recent studies suggest retention of the wild type U2AF1 allele is required for cell viability (Fei et al., BioRxiv, 2016). Interestingly, RUNX1 is the most commonly co-mutated gene in MDS patients with U2AF1 mutations, and U2AF1 and RUNX1 are also co-mutated in some AML patients. These findings suggest RUNX1 deficiency and U2AF1 mutation cooperate in the pathogenesis of MDS and AML. To test this hypothesis, we crossed Cre-based conditional Runx1 knockout mice (Runx1f/f) with mice carrying a newly developed Cre-based conditional U2af1-S34F mutation (U2af1+/S34F) to generate Runx1f/f, Mx1-Cre, U2af1+/S34Fmice, which express U2af1-S34F and deficient-Runx1 after inducing Cre from the Mx1 promoter with poly (I:C). We found that U2af1-S34F attenuated the Runx1-/--induced increase of myeloid cells in spleen and bone marrow, as well as the increase of progenitor (lineage-/Sca1-/C-kit+) and stem cells (lineage-/Sca1-/C-kit+). Competitive repopulation assays showed that combining the U2af1 mutation and Runx1 deficiency impaired the transplantation capacity of bone marrow progenitor cells, especially for the myeloid lineage. We further aged these mice to examine the cooperative effects of U2af1-S34F and Runx1 deficiency in disease progression, upon the treatment of a one time, low-dose N-ethyl-N-nitrosourea. Mx1-Cre, U2af1+/S34F mice didn't show survival defect when compared to control mice, while the Runx1f/f, Mx1-Cre mice developed MDS, as previously reported. Interestingly, of fourteen Runx1f/f, Mx1-Cre, U2af1+/S34F mice, two developed AML, and the rest developed MDS. Moreover, transplanted spleen and bone marrow cells from one of four MDS Runx1f/f, Mx1-Cre, U2af1+/S34F mice also developed AML in the recipients. Although Runx1f/f, Mx1-Cre mice also had MDS, their MDS cells did not develop into leukemia after transplantation. Our data therefore suggest that Runx1 deficiency and MDS-associated U2af1 mutation can cooperate in the genesis of AML from MDS. Disclosures No relevant conflicts of interest to declare.

Poor Outcome after Allogeneic Hematopoietic Stem Cell Transplantation for De Novo AML with Chromosome 7 Abnormalities: A Report for the ALWP of the European Group for Blood and Marrow Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 325-325
Author(s):  
Agnes Buzyn ◽  
Myriam Labopin ◽  
Jurgen Finke ◽  
Tapani Ruutu ◽  
G. Ehninger ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
De Novo ◽  
Conditioning Regimen ◽  
Chromosome 7 ◽  
Partial Deletion ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Advanced Phase ◽  
De Novo Aml

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many acute myeloid leukemia (AML) patients, especially those with high-risk features. However, for the latter, cure rates remain disappointing due to relapse and transplant related mortality. Since high-risk AML defines a heterogeneous group of patients, the aim of this study was to evaluate specifically the impact of chromosome 7 abnormalities on the outcome of patients transplanted for AML. From 1982 to 2005, 159 de novo AML patients were reported in the EBMT registry with a chromosome 7 abnormality. Median age was 40 years (16–67). FAB subtypes were various: 20 M0, 34 M1, 34 M2, 30 M4, 10 M5, 6 M6, 9 M7, 16 missing. Monosomy 7 was present in 86 patients (54%) either isolated (n=71) or associated to a complex karyotype (n=15), whereas 46% had partial deletion. HSCT was performed in complete remission (CR1) in 85 patients (53%) and for an advanced phase for 69 (43%) defined as either primary refractory (n=49) or progressive (n= 20). The donor was a match sibling (n=88), unrelated donor (MUD) (n=42), or mismatched UD (n=29). The conditioning regimen was myeloablative for 123 patients (77%), containing TBI for 82. Stem cell source was peripheral blood for 97 patients (61%). T cell depletion was performed for 54% of the transplants either in vivo (n=60) or in vitro (n=26). The median follow up of the cohort is 47 months. A GvHD grade II-IV occurred in 47 patients (30%) and III/IV in 28 patients (18%). Among 132 patients alive at day 100, 38% developed chronic GvHD. At time of analysis only 42 patients are alive. The main cause of death is relapse (57%). The univariate analysis shows that the probability of OS at 5 years is 43% for patients transplanted in CR as compared to 11% for advanced phase patients (p<0,0001), and is only 17% for patients with a monosomy 7 compared to 29% for patients with a partial deletion (p=0,007). The survival of patients with AML FAB subtypes M5, 6 or 7 is only 8% compared to 24% for other subtypes (p=0,03). The year of transplant, T cell depletion, type of donor, conditioning regimen, cell source, and patients age have no influence on survival. In the multivariate analysis, CR at transplant (p= 0,005) and partial deletion of chromosome 7 (p=0,02) are the only two factors associated with a better 5 years OS. In conclusion, patients with abnormalities of the chromosome 7 and specially those with monosomy 7 represent a very high risk group of AML patients after HSCT, mostly because of the relapse risk, suggesting a very poor graft-versus-leukemia (GvL) effect in this disease which does not seem to be improved by the use of an UD. Thus, new approaches attempting to decrease the relapse rate of de novo AML with chromosome 7 abnormalities after HSCT are urgently needed.

Molecular Characterization Of De Novo and Therapy-Related MDS/AML With Der(1;7)(q10;p10)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2585-2585
Author(s):  
Westman K Maj ◽  
Mette K. Andersen
Keyword(s):  
De Novo ◽  
Conflicts Of Interest ◽  
Chromosome 7 ◽  
Molecular Characteristics ◽  
Prognostic Impact ◽  
Monosomy 7 ◽  
Mutation Status ◽  
Exact Test ◽  
Molecular Abnormalities ◽  
Idh Mutations

Abstract Background The majority of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) has acquired cytogenetic and molecular abnormalities of diagnostic and prognostic importance. Lately, focus has been on genes involved in epigenetic regulation, such as IDH, TET2, ASXL1 and DNMT3A, in which mutations have been shown to affect prognosis. The subgroup of MDS/AML with chromosome 7 abnormalities, are associated with somatic mutations of the RUNX1 gene, and so far monosomy 7 and der(1;7)(q10;p10) have been regarded as similar cytogenetic entities because they both result in loss of 7q. However, we have recently shown that mutations of the IDH gene are significantly associated with der(1;7)(q10;p10), but are inversely correlated with other chromosome 7 abnormalities in therapy-related MDS (t-MDS) and AML (t-AML) (Westman et.al. Leukemia 2013; 27(4):957-9). The aim of the study was to further molecularly characterize a larger cohort of patients with der(1;7)(q10;p10) and to compare the frequency of IDH and other mutations to MDS/AML cases with monosomy 7 as the sole abnormality. Methods Genomic DNA from 19 de novo and therapy-related MDS/AML cases with der(1;7)(q10;p10) was analyzed for mutations of FLT3, NPM1, IDH1/2, RUNX1 and DNMT3A genes by Sanger sequencing. For comparison 22 cases with monosomy 7 were investigated for mutations of the same genes. Additional investigations of possible mutations of ASXL1 and TET2 are ongoing and will be presented. Statistical evaluations were performed using Fisherxs exact test (two-tailed) or Wilcoxonxs two-sample test. Results There was no difference between patients with der(1;7) and monosomy 7 in clinical characteristics such as sex, age, presentation as MDS or AML, or de novo or therapy-related disease (Table 1). In total, 14 of 19 patients with der(1;7)(q10;p10) had mutations of IDH, RUNX1 or DNMT3A. Seven patients had a mutation in only one of these 5 genes, while the remaining 7 patients had mutations in 2 of the genes (Table 1). Nine patients had RUNX1 mutations (47%), 7 patients had IDH mutations (37%), and 3 patients had DNMT3A mutations (16%). As for patients with monsomy 7, nine of 22 patients had mutations of IDH, RUNX1 or DNMT3A but only one of the patients had mutations in more than one gene (Table 1). Five patients had RUNX1 mutations (23%), 3 patients had DNMT3A mutations (14%), and one patient had a mutation of IDH1 (5%). No mutations were detected in NPM1 or FLT3 in any of the patients. When comparing molecular characteristics, mutations of RUNX1, IDH, and DNMT3A were significantly more common in patients with der(1;7) compared to patients with monosomy 7 (p=0.03). IDH mutations were significantly associated with der(1;7) (p=0.02), whereas there was no difference in the distribution of RUNX1 and DNMT3A mutations between patients with der(1;7) and patients with monosomy 7 (p= 0.1 and 0.7, respectively). There was no difference in mutation frequency between patients with de novo and therapy-related MDS/AML (p=0.3). Conclusions In MDS/AML with chromosome 7 abnormalities, IDH mutations are significantly associated with der(1;7) compared to cases with monosomy 7, whereas mutations of RUNX1 and DNMT3A are equally distributed between the two cytogenetic subgroups. This difference in mutation status of IDH supports that der(1;7) and monosomy 7 should not be regarded as similar entities and suggests that der(1;7) has a specific biological effect in leukemogenesis different from that of other chromosome 7 defects. Our findings are in line with a recent multicenter study showing different clinical outcomes for patients with der(1;7) compared to patients with -7/7q- (Ganster et.al., Prognostic impact of der(1;7) in MDS is different from del(7q), EHA 2013). More studies are needed to determine if der(1;7) and monosomy 7 show other molecular differences than IDH1/2 mutation status. Disclosures: No relevant conflicts of interest to declare.

Therapy-related myelodysplastic syndrome (t-MDS) following treatment of acute myeloid leukemia (AML)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17509-17509
Author(s):  
C. Arana-Yi ◽  
A. W. Block ◽  
S. N. Sait ◽  
L. A. Ford ◽  
M. Barcos ◽  
...  
Keyword(s):  
De Novo ◽  
Alkylating Agents ◽  
Autologous Transplantation ◽  
Chromosome 7 ◽  
World Health ◽  
Colony Stimulating Factor ◽  
Peripheral Blood Stem Cells ◽  
Monosomy 7 ◽  
De Novo Aml ◽  
Stimulating Factor

17509 Background: t-MDS is well described following treatment of lymphomas, solid tumors and acute promyelocytic leukemia. In contrast, it has been reported only rarely following treatment of AML, possibly because of the smaller percentage of long-term survivors or the difficulty of distinguishing t-MDS from AML relapse. Methods: Roswell Park Cancer Institute (RPCI) patients with a diagnosis of MDS by French-American-British or World Health Organization criteria following a diagnosis of AML were retrospectively reviewed. Results: Five adult patients treated for de novo AML between 1996 and 2005 developed MDS, representing less than 1% of 548 RPCI AML patients during those years. MDS presented as cytopenias and marrow dysplasia, occurred 11 to 101 (median 27) months after diagnosis of de novo AML, and was associated with chromosome 7 abnormalities, including monosomy 7 or del(7q), in all five. All had been treated with cytarabine and topoisomerase II inhibitors and three had received alkylating agents as part of autologous transplant regimens. All had received granulocyte colony-stimulating factor or granulocyte-monocyte colony-stimulating factor in conjunction with chemotherapy and/or autologous transplantation. Fluorescence in situ hybridization with the CEP 7 probe or the dual-color LSI D7S486 (7q31)/CEP 7 probe set did not demonstrate chromosome 7 abnormalities in marrow prior to MDS diagnosis nor in peripheral blood stem cells of patients who had undergone autologous transplantation prior to diagnosis of MDS. MDS has progressed slowly in all patients; it evolved to AML in two following 18 and 24 months. Conclusions: These cases further document t-MDS following AML therapy. Presence of chromosome 7 abnormalities in cases without, as well as with, prior alkylating agent therapy suggests possible association with the anti-metabolite cytarabine. No significant financial relationships to disclose.

scholarly journals Role of Genetic Evolution and Germline Mutations in SAMD9 and SAMD9L Genes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-33-SCI-33
Author(s):  
Jason R Schwartz ◽  
Marcin W. Wlodarski ◽  
Jeffery M. Klco
Keyword(s):  
Bone Marrow ◽  
Germline Mutation ◽  
Bone Marrow Failure ◽  
Hematopoietic Cells ◽  
Germline Mutations ◽  
Chromosome 7 ◽  
Chromosome Loss ◽  
Wild Type ◽  
In Vivo Models ◽  
Monosomy 7

Acquired deletions on chromosome 7 (monosomy 7/del7q) are common in myeloid neoplasms, especially pediatric MDS and AML. Although these tumors have historically been reported to occur within families, suggesting a genetic predisposition, the genetic lesion(s) that initiate these diseases has remained elusive until the last few years. Following a series of publications in which germline mutations in SAMD9 and SAMD9L were reported in a MIRAGE syndrome and Ataxia Pancytopenia syndrome, respectively, our group and others described similar heterozygous missense germline mutations in pediatric MDS, especially non-syndromic familial MDS with monosomy 7. Mutations in SAMD9 and SAMD9L have now also been reported in transient monosomy 7, inherited bone marrow failure and AML. Collectively, it is estimated that germline mutations in these genes are present in nearly 20% of children with MDS, with a strong enrichment in those with monosomy 7. Surprisingly, SAMD9 and SAMD9L are paralogous genes adjacently located on human chromosome 7 at band 7q21, and the monosomy 7 clone that expands in children universally lacks the pathologic germline variant. Expression of the mutant proteins in cells results in profound growth suppression, suggesting that there is strong selective pressure for hematopoietic cells to not express the mutant alleles. In addition to chromosome loss, additional methods that suppress expression of the pathologic allele have been described. These include copy neutral loss of heterozygosity (CN-LOH) with duplication of the wild-type allele or the somatic acquisition of additional mutations in cis with the germline mutation that counteract the growth suppressive effect of the germline mutation. The clinical phenotype is largely dictated by the revertant mutation in the dominant hematopoietic clone within the patient's bone marrow. Those with an expansion of a CN-LOH clone are more commonly asymptomatic, in contrast to those patients with a dominant monosomy 7 clone. Progression to higher grade MDS or AML is associated with the acquisition of additional somatic mutations including mutations in SETBP1, KRAS and RUNX1. The recognition of these germline mutations has had an immediate impact on the clinical management of children with MDS, including their family members, and ongoing clinical work in the pediatric MDS community is aimed at establishing guidelines for the pathologic diagnosis, clinical monitoring and treatment for these patients. In addition to these ongoing clinical pursuits, there is significant research interest in these genes, the function of their proteins in hematopoietic cells and how the germline mutations alter the function of the wild-type protein. The SAMD9 and SAMD9L proteins are largely uncharacterized and have been shown to be important in endocytosis, growth factor signaling and to have antiviral properties. Intriguingly, SAMD9 and SAMD9L are both induced by inflammatory signals, including interferons, suggesting a link between inflammatory stress and the disease phenotype. Ongoing studies are aimed at developing models, including in vitro and in vivo models, to understand the mechanisms by which these germline mutations can ultimately lead to the development of pediatric MDS and related disorders. Disclosures No relevant conflicts of interest to declare.

Molecular Epidemiological Study in Pediatric Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2015-2015
Author(s):  
Helene Lapillonne ◽  
S. Lejeune-Dumoulin ◽  
Paola Ballerini ◽  
A.S. Goetgheluck-Gadenne ◽  
Anne Auvrignon ◽  
...  
Keyword(s):  
Gene Expression ◽  
De Novo ◽  
Type I ◽  
Type Ii ◽  
Monosomy 7 ◽  
Female Ratio ◽  
Ras Mutations ◽  
De Novo Aml ◽  
Cebpa Mutations ◽  
11Q23 Abnormalities

Abstract It is hypothesized that AML arises from two cooperative types of mutations: type I mutations mainly induce proliferation and type II mutations involved in the maturation arrest. AML is a rare disease in children and few molecular data are available on pediatric AML. We therefore studied N-RAS, K-RAS, FLT3-ITD, FLT3 , C-KIT mutations (type I), and CEBPA mutations (type II) as well as FLT3, EVI-1 and WT1 gene expression in 77 de novo AML. Patients and methods: All the patients (aged 1 month-17 years, median age: 6.9 years, male/female ratio 1.26) were treated for de novo AML between 1995 and 2003 in two French institutions and prospectively enrolled in LAM91, LAM01 and APLs French collaborative protocols. According to the FAB classification the repartition was: M0:6.5%, M1: 5.2%, M2: 22%, M3: 13%, M4 :14.3%, M5 :30%, M7: 6.5% and unclassified :2.5%. Cytogenetics features according to the MRC classification were favorable, intermediate or poor in 25% (t(8;21) n=5; t(15,17) n=8, inv(16) n=5), 65% (normal n=20 and 11q23 abnormalities n=15) and 10% (−7, n=4) respectively. With a median follow-up of 26 months (range 2–98 months), Complete Remission was obtained in 92% (71/77) of patients, OS was 71% and EFS 61%. CEBPA, N-RAS, K-RAS, C-KIT and FLT3 mutations detection was performed by direct sequencing. FLT3, EVI-1 and WT1 transcripts were quantified by RQ-PCR. Results: (1) Frequency of N-RAS and K-RAS mutations were 11% (8/75) and 16% (12/75) respectively. RAS-mutated patients belonged to favorable (30%), intermediate (60%) and poor (10%) cytogenetic subgroups. In univariate analysis only N-RAS mutations is associated with adverse outcome (OS 37% vs 79%, p<0.05). (2) CEBPA mutations were found in 8% (6/75), mostly belonged to the intermediate cytogenetic risk subgroup (66%). (3) C-KIT mutations were observed in 4% (4/75) always associated with fusion CBFb/MYH11 transcript and excellent outcome. (4) FLT3-ITD and FLT3 Asp835 mutations were obtained in 12% (9/74) and 4% (3/74) of patients respectively. Cytogenetic subgroups were favorable (33%) and intermediate (67%). (5) At diagnosis FLT3 overexpression was detected in 34% (24/70) and 11q23 abnormalities were associated in 7/24 patients. (6) EVI-1 overexpression was found in 21% (16/76), belonged to intermediate (85%) and poor (15%) cytogenetic subgroups with a significant frequency in monosomy 7 (p<0.025). The EVI-1 expression was specifically expressed (p<0.001) in M5 and M7-FAB subtypes. (7) WT1 overexpression was detected in 81% (62/76). Conclusion: In total, 48% of de novo AML in children had a mutation in N-RAS, K-RAS, FLT3-ITD, FLT3 Asp835, C-KIT or CEBPA with a high frequency of RAS mutations (27%) compared to adult AML and a significantly bad survival. Additional gene expression quantification of EVI-1, FLT3 and WT1 allows MDR detection in 95% of patients.

Prolonged Survival of a Patient with De Novo Acute Myeloid Leukemia (AML) and Trisomy 13 with Intensive Chemotherapy and Autologous Peripheral Blood Transplantation (PBSCT): A Case Report.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4519-4519
Author(s):  
Nitin D. Joshi ◽  
Alpesh Amin ◽  
Rajneesh Nath
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Bone Marrow Biopsy ◽  
Induction Chemotherapy ◽  
Peripheral Blood ◽  
De Novo ◽  
Trisomy 13 ◽  
Autologous Pbsct ◽  
De Novo Aml ◽  
First Complete Remission

Abstract Trisomies are uncommon cytogenetic abnormalities in patient with de novo AML. Survival of patients with trisomy 13 ranges from 0.5 to 14.7 months. We present the treatment outcome of a 71-year-old man with de novo AML and trisomy 13 who had PBSCT in first complete remission. A 71-year Puerto Rican male was diagnosed with AML in April 2003. His CBC showed WBC count 177 K/mm3, hemoglobin 10.3 gm/dl, platelets 43 K/mm3 and blast cells 75%. Flow cytometry revealed that the leukemic blasts were CD33, CD13, CD11c and CD56 positive but negative for CD34. Cytogenetics failed to yield any metaphases. Peripheral blood FISH studies revealed trisomy 13 positivity in 300 of 325 cells analyzed. Patient received induction chemotherapy with high dose Ara-c (HiDAC) 3g/m2 QD x 5 doses and mitoxantrone 80mg/m2 on day # 2. Bone marrow done day 28 post induction chemotherapy revealed residual leukemic blasts. Cytogenetics showed that one out twenty metaphases had trisomy 13 along with translocation t (9:18) (q34; q10). 11.9% of cells had trisomy 13 by FISH analysis. The patient then received a second cycle of chemotherapy with HiDAC at 2 g/m2 Q12 x 12 doses. Bone marrow biopsy on day 35 following reinduction chemotherapy revealed normocellular-regenerating marrow in remission and FISH was negative for trisomy 13. On the third cycle of chemotherapy, patient received Etoposide 11 mg/kg. Neupogen was started on day #3 and 10.3 x 106 CD34 positive cells/kg were collected. The patient then underwent autologous PBSCT using Melphalan 160 mg/m2 as the preparative regimen. On Day +87 and Day +182 post transplant, bone marrow biopsy showed complete remission with FISH negative for trisomy 13. The patient is still alive 27 months after initial treatment and 22 months post PBSCT. Autologous PBSCT in first complete remission for AML with trisomy 13 may provide a superior survival than chemotherapy alone.

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