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

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.

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

Blood ◽

10.1182/blood.v80.11.2873.2873 ◽

1992 ◽

Vol 80 (11) ◽

pp. 2873-2882 ◽

Cited By ~ 75

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.

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Chromosomal Abnormalities in Philadelphia Chromosome (Ph)-Negative Metaphases Appearing during Imatinib Mesylate (IM) Therapy in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase.

Blood ◽

10.1182/blood.v106.11.1090.1090 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1090-1090 ◽

Cited By ~ 1

Author(s):

Elias Jabbour ◽

Hagop Kantarjian ◽

Susan O’Brien ◽

Srdan Verstovsek ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Myeloid Leukemia ◽

Chromosomal Abnormalities ◽

Philadelphia Chromosome ◽

Chromosome 7 ◽

Molecular Response ◽

Newly Diagnosed ◽

Trisomy 8 ◽

Chromosome Y ◽

Cytogenetic Abnormalities

Abstract The development of chromosomal abnormalities in the Ph-negative metaphases during IM therapy of CML has been recognized mostly in pts who failed prior therapy. Prior exposure to cytarabine has been suggested to be a predisposing factor. This phenomenon has not been yet assessed to date in patients with newly diagnosed CML and treated with IM. This is different from clonal evolution where the abnormalities are observed in the Ph-positive metaphases. We assessed the frequency and the significance of this event among 258 newly diagnosed pts with CML receiving IM (800 mg/d n=207, 400 mg/d n=51) as first line of therapy between March 2001 and April 2005. After a median follow-up of 30 months (range, 6–48 months), 19 pts (7%) developed 21 chromosomal abnormalities in Ph-negative metaphases. Thirteen (62%) of these abnormalities have been seen in 2 or more metaphases. The median time from the start of IM to appearance of abnormalities was 18 months (range, 3–36 months). The most common cytogenetic abnormalities were: loss of chromosome Y (n=7, 33%), trisomy 8 (n=3, 14%), and deletion of chromosome 7 (n=2, 10%). Excluding loss of chromosome Y abnormalities, the incidence was 5%. All pts achieved a major (Ph < 35%) cytogenetic (CG) response (complete cytogenetic response [CCGR] in 17 [89%] pts). Major molecular response (BCR-ABL/ABL ratio <0.05) was observed in 13 (68%) pts (including 2 with complete molecular response). In all but 4 pts these events have been transient and disappeared after a median of 4 months (range, 3–9 months). In 4 pts (loss of chromosome Y n=3, trisomy 8 n=1), they persisted for a median of 13+ months (range, 6+–24+ months). One pt developed acute myeloid leukemia (associated with -7); none of the other pts has any feature of myelodysplasia. After a median follow-up of 13 months (range, 1–42 months), 17 of the 19 pts are alive. One pt died after allogeneic stem cell transplantation, and one died after 6 months of CCGR from myocardial infarction. One pt lost response to IM. The remaining 16 pts are in major CG response at the last follow-up. We conclude that: 1) cytogenetic abnormalities occur in Ph-negative cells in a small fraction of patients (7%; 5% if loss of Y excluded) in newly diagnosed CML on IM; 2) in the majority of cases, they are transient with no clear clinical consequences; 3) in rare instances (loss of chromosome 7 only in our study) they could reflect the emergence of a new malignant clone necessitating and a close follow-up.

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Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations

Blood ◽

10.1182/blood-2010-05-283291 ◽

2010 ◽

Vol 116 (20) ◽

pp. 4086-4094 ◽

Cited By ~ 131

Author(s):

Wen-Chien Chou ◽

Huai-Hsuan Huang ◽

Hsin-An Hou ◽

Chien-Yuan Chen ◽

Jih-Luh Tang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

De Novo ◽

Human Leukocyte ◽

Normal Karyotype ◽

Trisomy 8 ◽

Disease Evolution ◽

Biological Features ◽

Sex Comb ◽

Acute Myeloid

Abstract Mutations in the additional sex comb-like 1 (ASXL1) gene were recently shown in various myeloid malignancies, but they have not been comprehensively investigated in acute myeloid leukemia (AML). In this study, we analyzed ASXL1 mutations in exon 12 in 501 adults with de novo AML. ASXL1 mutations were detected in 54 patients (10.8%), 8.9% among those with normal karyotype and 12.9% among those with abnormal cytogenetics. The mutation was closely associated with older age, male sex, isolated trisomy 8, RUNX1 mutation, and expression of human leukocyte antigen–DR and CD34, but inversely associated with t(15;17), complex cytogenetics, FLT3–internal tandem duplication, NPM1 mutations, WT1 mutations, and expression of CD33 and CD15. Patients with ASXL1 mutations had a shorter overall survival than patients without, but the mutation was not an independent adverse prognostic factor in multivariate analysis. Sequential analyses showed that the original ASXL1 mutations were lost at relapse and/or refractory status in 2 of the 6 relapsed ASXL1-mutated patients studied, whereas 2 of the 109 ASXL1-wild patients acquired a novel ASXL1 mutation at relapse. In conclusion, AML bearing ASXL1 mutations showed distinct clinical and biological features. The ASXL1 mutation status can change during disease evolution in a few patients.

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Cytogenetic and Morphological Analysis of De Novo Acute Myeloid Leukemia in Adults: A Single Center Study in Jordan

Balkan Journal of Medical Genetics ◽

10.2478/v10034-012-0001-3 ◽

2012 ◽

Vol 15 (1) ◽

pp. 5-10

Author(s):

M Ayesh ◽

B Khassawneh ◽

I Matalkah ◽

K Alawneh ◽

S Jaradat

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Morphological Analysis ◽

De Novo ◽

Chromosomal Abnormalities ◽

Single Center ◽

Trisomy 8 ◽

Single Center Study ◽

Acute Myeloid ◽

Center Study

Cytogenetic and Morphological Analysis of De Novo Acute Myeloid Leukemia in Adults: A Single Center Study in JordanAcute myeloid leukemia (AML) in adults is known to be a heterogeneous disease with diverse chromosomal abnormalities. Some of these abnormalities are found with a high incidence in specific ethnic groups and in certain geographical areas. We report the results of cytogenetic studies of 35 adult Jordanian Arab patients withde novoAML diagnosed according to the French-American-British (FAB) criteria. Four patients did not have metaphases secondary to hypocellular bone marrow. The most common morphological subtype was M5 (55%) followed by M3 (19%). Cytogenetic abnormalities were present in 20 patients (65%); t(15;17) translocation in six patients (19%), inv(16) in four patients (13%), t(11;17) in two patients (4%), and the t(8;21) translocation was not present in any patient. Trisomy 8 was the most common numerical chromosomal abnormality [four patients (13%)].There were variations and similarities with similar ethninc Arab populations. The most common chromosomal abnormalities were t(15;17), +8 and inv(16). Further and larger crossborder studies are needed.

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Acute Myeloid Leukemia With t(8;21)/RUNX1-RUNX1T1 demonstrate a High Number Of Secondary Genetic Lesions: Frequency and Impact On Clinical Outcome

Blood ◽

10.1182/blood.v122.21.2565.2565 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2565-2565

Author(s):

Maria Theresa Krauth ◽

Christiane Eder ◽

Tamara Alpermann ◽

Wolfgang Kern ◽

Claudia Haferlach ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Chromosomal Aberrations ◽

Myeloid Leukemia ◽

De Novo ◽

Chromosomal Abnormalities ◽

Trisomy 8 ◽

Employment Equity ◽

Equity Ownership ◽

De Novo Aml ◽

Acute Myeloid

Abstract Background Translocation t(8;21) with the resulting RUNX1-RUNX1T1 rearrangement is one of the most common chromosomal abnormalities in acute myeloid leukemia (AML). Although it is generally associated with a favourable prognosis, many additional genetic lesions may impact on outcome. Aim To assess the frequency and clinical impact of additional mutations and chromosomal aberrations in AML with t(8;21)/RUNX1-RUNX1T1. Methods We analyzed 139 patients (pts) who were referred to our laboratory for diagnosis of AML between 2005 and 2012 (65 females, 74 males; median age 53.3 years, range 18.6 - 83.8 years). All pts were proven to have t(8;21)/RUNX1-RUNX1T1 by a combination of chromosome banding analysis, fluorescence in situ hybridisation and RT-PCR. Analysis of mutations in ASXL1, FLT3-TKD, KIT (D816, exon8-11), NPM1, IDH1 and IDH2, KRAS, NRAS, CBL, and JAK2 as well as of MLL-PTD and FLT3-ITD was performed in all pts. Results 107/139 pts were classified according to FAB criteria (77.0%). 34/107 had AML M1 (31.8%) and 73/107 AML M2 (68.2%). 117/139 had de novo AML (84.2%), 22/139 had therapy-related AML (t-AML) (15.8%). 69/139 (49.6%) pts had at least one molecular alteration in addition to RUNX1-RUNX1T1, 23/69 (33.3%) had two or more additional mutations. Most common were mutations (mut) in KIT (23/139; 16.5%), followed by NRAS (18/139; 12.9%) and ASXL1 (16/139; 11.5%). FLT3-ITD and mutations in FLT3-TKD, CBL, and KRAS were found in 4.3% - 5.0% of all pts, whereas mutations in IDH2 and JAK2 were detectable in 3.6% and 2.9%, respectively. IDH1 mutations were found in only 0.7% (1/139). NPM1mut and MLL-PTD were mutually exclusive of RUNX1-RUNX1T1. FLT3-ITD as well as FLT3-TKD were exclusive of ASXL1 mutations. With exception of FLT3-ITD, which was only present in de novo AML, there was no difference in mutation frequencies between de novo AML and t-AML. 69.8% (97/139) pts had at least one chromosomal aberration in addition to t(8;21)(q22;q22). Most frequent was the loss of either X- or Y-chromosome (together 46.8%), followed by del(9q) (15.1%), and trisomy 8 (5.8%). FLT3-ITD, FLT3-TKD and trisomy 8 were found to be mutually exclusive. The number of secondary chromosomal aberrations did not differ significantly between pts with de novo AML and t-AML, showing only a trend towards higher frequency of -Y, del(9q), and trisomy 8 in pts with t-AML. Survival was calculated in pts who received intensive treatment (n=111/139, 79.9%; median follow-up 26.9 months; 2-year survival rate 73.4%). With exception of KITD816 mutation, which had a negative impact on overall survival in pts with de novo AML (2-year survival rate 64.2% vs. 82.3%, p=0.03), none of the other 13 mutations significantly influenced outcome, not even in case of 2 or more coexistent mutations. Also, no influence of additional chromosomal aberrations on survival was found. In selected cases (n=21/139), we compared dynamic changes in the patterns of genetic lesions at diagnosis and at relapse. In 14/21 (66.7%) pts the initial molecular mutation pattern changed at relapse. Mutations commonly gained at relapse were KIT mutations (6/21, 28.6%), followed by ASXL1 and IDH1R132 (each 2/21, 9.5%). FLT3-ITD, CBL, NRAS and JAK2 mutations emerged in 1/21 patients (4.8%) each. Loss of a mutation at relapse has been observed in KIT, ASXL1, and NRAS (each 2/21, 9.5%), as well as in KRAS, FLT3-ITD and FLT3-TKD (each 1/21, 4.8%). Concerning chromosomal alterations at relapse, 7/21 pts (33.3%) showed a change of their initial cytogenetic pattern, mostly shifting to a more complex karyotype (gain of chromosomal aberrations: 5/21, 23.8%; loss of chromosomal aberrations: 2/21, 9.5%). In all cases, t(8;21)(q22;q22)/RUNX1-RUNX1T1 remained stable at time of relapse. Conclusions 1) 50% of t(8;21)/RUNX1-RUNX1T1 positive pts had at least one additional molecular mutation and almost 70% showed additional chromosomal abnormalities. 2) KIT was the most frequent additional molecular mutation, followed by NRAS and ASXL1. 3) The only additional genetic marker with a significant adverse prognostic impact was KITD816 mutation. Disclosures: Krauth: MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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A Compendium of Cytogenetic Abnormalities in Myelofibrosis: Molecular and Phenotypic Correlates in 826 Patients

Blood ◽

10.1182/blood.v124.21.403.403 ◽

2014 ◽

Vol 124 (21) ◽

pp. 403-403

Author(s):

Emnet A Wassie ◽

Christy Finke ◽

Naseema Gangat ◽

Terra L Lasho ◽

Animesh Pardanani ◽

...

Keyword(s):

Conflicts Of Interest ◽

International System ◽

Normal Karyotype ◽

Primary Myelofibrosis ◽

World Health ◽

Trisomy 8 ◽

Abnormal Karyotype ◽

Cytogenetic Abnormalities ◽

Chromosome 1Q ◽

Favorable Prognosis

Abstract Background : Recent studies have suggested significant associations between karyotype and certain molecular or phenotypic features in primary myelofibrosis (PMF). In the current study of 835 consecutive patients, we examined the spectrum and prevalence of cytogenetic abnormalities in PMF and their molecular and phenotypic correlates. Methods : PMF diagnosis was according to World Health Organization criteria. Cytogenetic analysis and reporting was done according to the International System for Human Cytogenetic Nomenclature. Statistical analyses considered clinical and laboratory parameters obtained at time of cytogenetic studies. Spectrum and frequency of cytogenetic abnormalities : Analyzable metaphases were obtained in 826 (99%) of 835 patients studied; 681(82%) had ≥20 metaphases analyzed. 352 (42.6%) patients had abnormal karyotype, including 240 (68.2%) sole, 64 (18.2%) two and 48 (13.6%) complex; comparison of these groups revealed lower platelet count (p<0.01), higher DIPSS-plus score (p=0.03) and higher percentage of younger patients (p=0.04) with complex abnormalities. Monosomal karyotype was noted in 20 (5.7%) patients. Approximately 150 individual abnormalities were identified; most frequent were 20q- (23.3%), 13q- (18.2%), +8 (11.1%), +9 (9.9%), duplication of chromosome 1q (9.7%) and -7/7q- (7.1%). Other notable abnormalities including i(17q) (1.4%), 12p- (1.1%) and inv(3) (0.6%) were much less frequent. Trisomy 8 was the most frequent in the context of complex abnormality (25%). Among the 500 patients seen within one year of initial diagnosis, 179 (35.8%) had abnormal karyotype, which included 121 (67.6%) sole, 31 (17.3%) two and 27 (15.1%) complex abnormalities; the most common abnormalities were 20q- (24.6%), 13q- (15.1%), +8 (14%) and +9 (10%) whereas 11q- (1.7%), i(17q) (1.1%), inv(3) (0.6%), and 12p- (0.6%) were infrequent. Molecular correlates : 476 patients were annotated for JAK2, CALR and MPL mutations; abnormal karyotype frequencies were 43% in JAK2, 42% CALR, 33% MPL mutated and 34% triple-negative cases (p=0.3). 13q- was associated with mutant CALR (p=0.03) and +9 with mutant JAK2 (p=0.02). Subsets of patients were also screened for ASXL1, EZH2, IDH, SRSF2, U2AF1, and SF3B1 mutations; in all instances, mutational frequencies were higher in patients with normal karyotype, reaching significance with ASXL1 (p=0.02) and U2AF1 (p=0.01). Mutant SRSF2 was associated with 20q- (p=0.02). Phenotypic correlates : Phenotypic correlates included abnormal karyotype with anemia (p=0.02), leukopenia (p<0.01) and thrombocytopenia (p<0.01); complex karyotype with younger age (p=0.04) and thrombocytopenia (p<0.01); leukopenia with 20q-, +8 and -7/7q-; and thrombocytopenia with 20q- and -7/7q-. Cytopenias were less likely to occur with 13q- (p<0.01), which was instead associated with thrombocytosis (p<0.01). 20q- was associated with lower incidence of marked leukocytosis (p=0.02). Trisomy 8 was associated with lower incidences of constitutional symptoms (p<0.01) and marked splenomegaly (p<0.01). Conclusions : The association of 13q- with CALR mutations in PMF might underlie its association with both thrombocytosis and favorable prognosis. The association of +9 with JAK2 mutations might reflect selective clonal advantage through JAK2V617F dosage enhancement or mutation-induced chromosomal instability. The association of 20q- with mutant SRSF2 and thrombocytopenia warrant further clarification of its reported association with favorable prognosis. Disclosures No relevant conflicts of interest to declare.

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Acute Erythroid Leukemia (AEL): A Clinical, Morphological, Cytogenetic and Follow-Up Study of 69 Patients.

Blood ◽

10.1182/blood.v106.11.3271.3271 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3271-3271

Author(s):

Elisa Luño ◽

Carmen Sanzo ◽

Francesc Sole ◽

Mirian Gonzalez ◽

Isabel Granada ◽

...

Keyword(s):

De Novo ◽

Chromosomal Abnormalities ◽

Remission Rate ◽

Normal Karyotype ◽

Intensive Chemotherapy ◽

Old Patients ◽

Monosomy 7 ◽

Risk Of Death ◽

Multilineage Dysplasia ◽

Risk Of Relapse

Abstract AEL is a uncommon type of acute leukemia. The subjects in this retrospective study were 69 patients diagnosed as having AEL to assess the incidence of different subtypes, detect prognostic factors, and compare there profile with others AML. 63 patients (82,5%) were diagnosed of erythroleukemia (EL) and 7 (17,5%) were pure erythroid leukemia according to WHO classification. 63,6% of EL presented erythroid maturation (immature/mature erythroid ratio <25%), and 36,4% >25%. Three of seven pure erythroid leukemia showed immature erythroid precursors identified by ultrastructural methods, and four had erythroid cells at all maturation stage. 49 (71%) were de novo AEL, only 3 pure erythroid leukemia, 9 (13%) were therapy related, in nine (13%) was preceded by a MDS, and 2 suffer a BC-CML, all of this later, pure erythroid leukemia. The three cases of pure erythroid proliferations with only immature precursors were two Down’s syndrome, both 2 years old, and one BC-CML. The chromosomal abnormalities were classified by SWOG and MRC. BC-CML were excluded from survival analyses. A p value <0.01 was considered significant. There were 38 males and 31 females. The median age was 62 years. The medians hemoglobin 80 g/l; white cell 3,8x109/L; absolute neutrophil 1,0x109/L and platelet 36,0x109/L. Multilineage dysplasia were present in 74,5% (41/55). The overall incidence of chromosomal abnormalities was 79,7%(55/69). 35(50,7%) patients had complex karyotype, 26/49(53,1%) in de novo acute erythroid leukemia. Single abnormalities include 4 monosomy 7, 2 del(5q), two +8, two + 21. 39/64 patients (60,9%) received intensive chemotherapy (9 were consolidated with SCT) and 19/39 (48,7%) achieved CR. Remission rate was 83,3% for normal karyotype and 85,7% and 62,5% for intermediate cytogenetic groups according SWOG (p=0,003) and MCR(p=0,037). The median OS was 4 months with a projected actuarial DFS at 12 months 32,5%. Patients under 40 years (p=0,0001) with normal karyotype (p=0.0003) or intermediate SWOG (p=0.0002) or MRC (p=0.0019) citogenetic groups, who received intensive chemotherapy (p<0.0001) had a longer OS, and younger patients (p=0.0056) with normal karyotype (p=0.0038), or intermediate SWOG (p=0.0006) or MRC (p=0.039) citogenetic groups, consolidated with SCT (p=0.0023) showed the longest DFS. Multivariate analysis showed that only karyotype, is a powerful prognostic indicator both for OS and DFS, besides treatment for OS and age for DFS. The higher risk of relapse is for ≥65 years old patients (OR=2,84) with unknown (OR=7,86) or unfavourable (OR=4,29) SWOG groups and the higher risk of death is for unfavourable (OR=4,33) SWOG groups and those treat with supportive care (OR =3,31). When AEL were compared with a consecutive series of 339 de novo AML, 109 of them ≥ 65 years, and 68 therapy related AML, EL excluded, these series are similar for age and sex but AEL present more frequent multilineage dysplasia (p<0,001), and SWOG or MRC unfavourable citogenetic groups (p<0,001), beside the low remission rate, high risk of relapse and death, was similar at elderly patients AML and therapy related AML.

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Is Acute Erythroid Leukemia a Transitional Stage from MDS to AML?: A Study by Fluorescence in Situ Hybridization and Cytogenetics

Blood ◽

10.1182/blood.v112.11.4867.4867 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4867-4867

Author(s):

Sang Mee Hwang ◽

Sang-ho Lee ◽

Seong_Ho Kang ◽

Seonyang Park ◽

Sung-Soo Yoon ◽

...

Keyword(s):

Myeloid Leukemia ◽

Chromosomal Abnormalities ◽

Transitional Stage ◽

Trisomy 8 ◽

Genetic Changes ◽

Chromosomal Changes ◽

French American British ◽

5Q Deletion ◽

Acute Myeloid

Abstract Background: Chromosomal abnormalities of acute erythroid leukemia (AEL) are reported to be complex and nonspecific. We compared the cytogenetic abnormalities of AEL to other subtypes of acute myeloid leukemia (AML) by G- band karyotyping and fluorescence in situ hybridization (FISH) techinique using 18 probes. Methods: 384 patients diagnosed with AML between January 2000 and December 2007 were classified morphologically by French-American-British classification. G-band karyotyping and FISH for 4 recurrent chromosomal abnormalities in AML [AML/ETO rearrangement, PML/RARa rearrangement, MLL rearrangement, inv(16)] were performed. To verify whether common cytogenetic abnormalities of myelodysplastic syndrome (MDS) were present in AEL, FISH for 5q deletion, 7q deletion, trisomy 8 and gain of 1q were performed on bone marrow nucleated cells of 25 patients with AEL. To evaluate the numerical chromosomal changes, ten additional FISH tests were done. Chromosomal enumeration probes (CEP) were primarily used and in case where there were no CEP available, probes for chromosomal rearrangement were surrogately used. Results: Incidence of recurrent genetic changes of AML [AML/ETO, PML/RARA, MLL, inv(16)] was 0% in AEL, while the incidence of AML/ETO, PML/RARA, MLL and inv(16) rearrangement in AML excluding AEL was 12.8%, 12.7%, 5.0%, 4.6%, respectively. Frequencies of numerical chromosomal changes were 11.8% in AML excluding AEL and 44% in AEL, showing significantly higher incidence of numerical changes in AEL. Frequencies of cytogenetic changes, which are common in MDS, were 20% for 5q deletion, 32% for trisomy 8, 16% for 1q gain among AEL patients. In total, 40% of the AEL patients showed similar chromosomal changes to MDS. By G-banding, 32% of the AEL patients showed numerical change of chromosome 8 and 20% for chromosome 5. However, numerical chromosomal changes by G-banding were not statistically different between AEL and other AML, while >3 complex chromosomal changes were significantly higher in AEL. (P=0.001) Out of 25 AEL patients, 4 patients (16%) were transformed from MDS and 1 patient (4%) transformed to other subtype of AML during treatment. Discussions: Numerical chromosomal change was the most predominant genetic change of AEL, while recurrent genetic changes of AML were not found in AEL. Instead, AEL patients showed similar chromosomal changes to MDS. This implies that AEL subtype of AML is rather a separate disease entity from the other types of AML, more within the spectrum of MDS. We infer that AEL is a transitional stage from MDS to AML. Table 1. General aspects and the summary of the results of AML and AEL* Characteristics AML AEL Abbreviations: AML, Acute myeloid leukemia; FAB, French-American-British classification; AEL, acute erythroid leukemia * AEL diagnosed by WHO criteria ¢” FISH was done on available specimen only ¢Ô Ploidy changes were determined by 18 kinds of probes in AEL, and 4 kinds of Probes in AML subtypes excluding AEL Gender female 161 41.9% 6 22.2% male 223 58.1% 21 77.8% total 384 100.0% 27 100.0% FAB classification M0 16 4.2% M1 43 11.2% M2 124 32.3% M3 43 11.2% M4 81 21.2% M5 17 4.4% M6 27 7.0% M7 7 1.8% undetermined 26 6.8% AML excluding AEL AEL Age, years (median) 15–77 (51) 17–84 (60) <60 248 69.5% 11 40.7% °Ã60 109 30.5% 16 59.3% Recurrent genetic abnormalities ¢” PML/RARA 43/338 12.7% 0/27 0.0% AML/ETO 42/327 12.8% 0/27 0.0% inv(16) 12/259 4.6% 0/27 0.0% MLL 16/319 5.0% 0/27 0.0% Abnormal karyotype 85/356 23.9% 13/27 48.1% Ploidy change by FISH ¢Ô 41/348 11.8% 14/25 56.0%

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Integrated Genomic Analysis Identifies UBTF Tandem Duplications As a Subtype-Defining Lesion in Pediatric Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-155134 ◽

2021 ◽

Vol 138 (Supplement 2) ◽

pp. LBA-4-LBA-4

Author(s):

Masayuki Umeda ◽

Jing Ma ◽

Benjamin J. Huang ◽

Kohei Hagiwara ◽

Tamara Westover ◽

...

Keyword(s):

Myeloid Leukemia ◽

Research Funding ◽

De Novo ◽

Screening Method ◽

Normal Karyotype ◽

Rna Seq ◽

Trisomy 8 ◽

De Novo Aml ◽

Pediatric Aml ◽

Tandem Duplications

Abstract Children with acute myeloid leukemia (AML) have a dismal prognosis due to a high relapse rate; however, the molecular basis leading to relapsed pediatric AML has not yet been fully characterized. To define the spectrum of alterations common at relapse, we performed integrated profiling of 136 relapsed pediatric AML cases with RNA sequencing (RNA-seq), whole-genome sequencing, and target-capture sequencing. In addition to well-characterized fusion oncoproteins, such as those involving KMT2A (n=36, 26.5%) or NUP98 (n=18, 13.2%), we also identified somatic mutations in UBTF (upstream binding transcription factor) in 12 of 136 cases (8.8%) of this relapsed cohort. Somatic alterations of the UBTF gene, which encodes a nucleolar protein that is a component of the RNA Pol I pre-initiation complex to ribosomal DNA promoters, have rarely been observed in AML. In our cohort, all alterations can be described as heterozygous in-frame exon 13 tandem duplications (UBTF-TD), either at the 3' end of exon 13 of UBTF or of the entire exon 13 (Fig. A). As we noticed limited detection in our pipeline as a result of complex secondary indels alongside the duplications, we established a soft-clipped read-based screening method to detect UBTF-TD more efficiently. Applying the screening to RNA-seq data of 417 additional pediatric AMLs from previous studies and our clinical service, we identified 15 additional UBTF-TDs, many of which have not been previously reported. At the amino acid level, UBTF-TDs caused amino acid insertions of variable sizes (15-181 amino acids), duplicating a portion of high mobility group domain 4 (HMG4), which includes short leucine-rich sequences. UBTF-TD AMLs commonly occurred in early adolescence (median age: 12.6, range: 2.4-19.6), and 19 of the total 27 cases had either normal karyotype (n=12) or trisomy 8 (n=7). UBTF-TD is mutually exclusive from other recurrent fusion oncoproteins, such as NUP98 and KMT2A rearrangements (Fig. B), but frequently occurred with FLT3-ITD (44.4%) or WT1 mutations (40.7%). The median variant allele fraction (VAF) of the UBTF-TD was 48.0% (range: 9.7-66.7%). In four cases with data at multiple disease time points, the identical UBTF-TDs were present at high allele fractions at all time points, suggesting that UBTF-TD is a clonal alteration. tSNE analysis of the transcriptome dataset showed that UBTF-TD AMLs share a similar expression pattern with NPM1 mutant and NUP98-NSD1 AML subtypes, including NKX2-3 and HOXB cluster genes (Fig. C) . Altogether, these findings suggest that UBTF-TD is a unique subtype of pediatric AML. To address the impact of UBTF-TD expression in primary hematopoietic cells, we introduced UBTF-TD and UBTF wildtype expression vectors into cord blood CD34+ cells via lentiviral transduction. UBTF-TD expression promotes colony-forming activity and cell growth, yielding cells with a persistent blast-like morphology (Fig. D). Further, transcriptional profiling of these cells demonstrated expression of HOXB genes and NKX2-3, similar to UBTF-TD AMLs in patients, indicating that UBTF-TD is sufficient to induce the leukemic phenotype. To investigate the prevalence of UBTF-TDs in larger de novo AML cohorts, we applied the above UBTF-TD screening method to the available de novo AML cohorts of TCGA (n=151, adult), BeatAML (n=220, pediatric and adult), and AAML1031 (n=1035, pediatric). We identified UBTF-TDs in 4.3% (45/1035) of the pediatric AAML1031 cohort, while the alteration is less common (0.9%: 3/329, p=0.002) in the adult AML cohorts (Fig. E). In the AAML1031 cohort, UBTF-TDs remain mutually exclusive with known molecular subtypes of AML and commonly occur with FLT3-ITD (66.7%) and WT1 (40.0%) mutations and either normal karyotype or trisomy 8. The presence of UBTF-TDs in the AAML1031 cohort is associated with a poor outcome (Fig. F, median overall survival, 2.3 years) and MRD positivity; multivariate analysis revealed that UBTF-TD and WT1 are independent risk factors for overall survival within FLT3-ITD+ AMLs. In conclusion, we demonstrate UBTF-TD defines a unique subtype of AMLs that previously lacked a clear oncogenic driver. While independent of subtype-defining oncogenic fusions, UBTF-TD AMLs are associated with FLT3-ITD and WT1 mutations, adolescent age, and poor outcomes. These alterations have been under-recognized by standard bioinformatic approaches yet will be critical for future risk-stratification of pediatric AML. Figure 1 Figure 1. Disclosures Iacobucci: Amgen: Honoraria; Mission Bio: Honoraria. Miller: Johnson & Johnson's Janssen: Current Employment. Mullighan: Pfizer: Research Funding; Illumina: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Amgen: Current equity holder in publicly-traded company.

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Current Cytogenetic Abnormalities in Acute Myeloid Leukemia

Chromosomal Abnormalities ◽

10.5772/intechopen.91425 ◽

2020 ◽

Author(s):

Mounia Bendari ◽

Nisrine Khoubila ◽

Siham Cherkaoui ◽

Nezha Hda ◽

Meryem Qachouh ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chromosomal Abnormalities ◽

Cytogenetic Study ◽

Chromosomal Rearrangements ◽

Normal Karyotype ◽

Cytogenetic Abnormalities ◽

Next Generation Sequencing Technology ◽

Health Organization ◽

Acute Myeloid

Cytogenetic abnormalities are frequently reported in the literature describing the presence of chromosomal rearrangements in important cases of acute myeloid leukemia (AML); the rate can reach 50–60% of cases of AML. Cytogenetic abnormalities represent an important prognosis factor, their analysis is crucial for AML; cytogenetic study permits to classify prognostic groups and indicate the treatment strategy and helps to improve the outcome of these patients and to increase their chances of cure. Hundreds of uncommon chromosomal aberrations from AML exist. This chapter summarizes chromosomal abnormalities that are common and classifies AML according to the World Health Organization (WHO) classifications from 2008 to 2016; we will discuss briefly gene mutations detected in normal karyotype (NK) AML by cutting-edge next-generation sequencing technology, like FLT3-ITD, nucleophosmin (NPM1), CCAAT/enhancer-binding protein alpha (CEBPA), and other additional mutations.

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