scholarly journals Trisomy 13: a new recurring chromosome abnormality in acute leukemia

Blood ◽  
1990 ◽  
Vol 76 (8) ◽  
pp. 1614-1621 ◽  
Author(s):  
H Dohner ◽  
DC Arthur ◽  
ED Ball ◽  
RE Sobol ◽  
FR Davey ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosome Abnormality ◽  
Cell Receptor ◽  
Trisomy 13 ◽  
Lymphoid Leukemia ◽  
High Incidence ◽  
T Cell Receptor Beta ◽  
Hematopoietic Precursor

Abstract A new recurring chromosome abnormality was identified in 8 of 621 consecutive successfully karyotyped adults with de novo acute leukemia. These eight patients had trisomy 13 as the sole cytogenetic abnormality. On central morphologic review, five cases were classified as subtypes of acute myeloid leukemia, one as acute mixed lymphoid and myeloid leukemia, one as acute lymphoid leukemia, and one as acute undifferentiated leukemia. Blasts of all eight cases expressed one or more myeloid differentiation antigens. Three also expressed T-lineage- associated antigens; however, none of these had rearrangement of the T- cell receptor beta, gamma, or delta genes. Four of six cases tested were TdT positive. All eight patients with trisomy 13 were treated with intensive induction chemotherapy; only three entered a short-lived complete remission. Survival of patients with trisomy 13 ranged from 0.5 to 14.7 months, and was significantly shorter than that of the remaining patients (median 9.5 v 16.2 months, P = .007). We conclude that trisomy 13 is a rare, recurring clonal chromosome abnormality in acute leukemia associated with a poor prognosis. Malignant transformation of an immature hematopoietic precursor cell is suggested by the expression of antigens characteristic of both the myeloid and lymphoid lineage, the high incidence of TdT positivity, and the morphologic heterogeneity in these leukemias.

scholarly journals Trisomy 13: a new recurring chromosome abnormality in acute leukemia

Blood ◽  
1990 ◽  
Vol 76 (8) ◽  
pp. 1614-1621 ◽  
Author(s):  
H Dohner ◽  
DC Arthur ◽  
ED Ball ◽  
RE Sobol ◽  
FR Davey ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosome Abnormality ◽  
Cell Receptor ◽  
Trisomy 13 ◽  
Lymphoid Leukemia ◽  
High Incidence ◽  
T Cell Receptor Beta ◽  
Hematopoietic Precursor

A new recurring chromosome abnormality was identified in 8 of 621 consecutive successfully karyotyped adults with de novo acute leukemia. These eight patients had trisomy 13 as the sole cytogenetic abnormality. On central morphologic review, five cases were classified as subtypes of acute myeloid leukemia, one as acute mixed lymphoid and myeloid leukemia, one as acute lymphoid leukemia, and one as acute undifferentiated leukemia. Blasts of all eight cases expressed one or more myeloid differentiation antigens. Three also expressed T-lineage- associated antigens; however, none of these had rearrangement of the T- cell receptor beta, gamma, or delta genes. Four of six cases tested were TdT positive. All eight patients with trisomy 13 were treated with intensive induction chemotherapy; only three entered a short-lived complete remission. Survival of patients with trisomy 13 ranged from 0.5 to 14.7 months, and was significantly shorter than that of the remaining patients (median 9.5 v 16.2 months, P = .007). We conclude that trisomy 13 is a rare, recurring clonal chromosome abnormality in acute leukemia associated with a poor prognosis. Malignant transformation of an immature hematopoietic precursor cell is suggested by the expression of antigens characteristic of both the myeloid and lymphoid lineage, the high incidence of TdT positivity, and the morphologic heterogeneity in these leukemias.

Cell lineage analysis of acute leukemia relapse uncovers the role of replication-rate heterogeneity and microsatellite instability

Blood ◽  
2012 ◽  
Vol 120 (3) ◽  
pp. 603-612 ◽  
Author(s):  
Liran I. Shlush ◽  
Noa Chapal-Ilani ◽  
Rivka Adar ◽  
Neta Pery ◽  
Yosef Maruvka ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Cell Lineage ◽  
Cell Subpopulation ◽  
Lymphoid Leukemia ◽  
High Throughput Method ◽  
Leukemia Relapse ◽  
Almost All ◽  
Lineage Trees

Abstract Human cancers display substantial intratumoral genetic heterogeneity, which facilitates tumor survival under changing microenvironmental conditions. Tumor substructure and its effect on disease progression and relapse are incompletely understood. In the present study, a high-throughput method that uses neutral somatic mutations accumulated in individual cells to reconstruct cell lineage trees was applied to hundreds of cells of human acute leukemia harvested from multiple patients at diagnosis and at relapse. The reconstructed cell lineage trees of patients with acute myeloid leukemia showed that leukemia cells at relapse were shallow (divide rarely) compared with cells at diagnosis and were closely related to their stem cell subpopulation, implying that in these instances relapse might have originated from rarely dividing stem cells. In contrast, among patients with acute lymphoid leukemia, no differences in cell depth were observed between diagnosis and relapse. In one case of chronic myeloid leukemia, at blast crisis, most of the cells at relapse were mismatch-repair deficient. In almost all leukemia cases, > 1 lineage was observed at relapse, indicating that diverse mechanisms can promote relapse in the same patient. In conclusion, diverse relapse mechanisms can be observed by systematic reconstruction of cell lineage trees of patients with leukemia.

scholarly journals Simultaneous or sequential expression of lymphoid and myeloid phenotypes in acute leukemia

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 142-148 ◽  
Author(s):  
PB Neame ◽  
P Soamboonsrup ◽  
G Browman ◽  
RD Barr ◽  
N Saeed ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Differentiation Markers ◽  
Lymphoid Leukemia ◽  
Chromosome Marker ◽  
Fab Classification ◽  
Blast Cells ◽  
French American British

Abstract Acute mixed myeloid-lymphoid leukemia is uncommon. We report four cases in which myeloid and lymphoid cell markers were observed simultaneously or sequentially when 94 patients with acute leukemia were phenotyped according to the French-American-British (FAB) classification system, with cytochemical stains, and with immunologically defined differentiation markers (identified by monoclonal antibodies and antiterminal deoxynucleotidyl transferase [TdT]). In one case, conversion from acute lymphoblastic leukemia to acute myeloid leukemia was noted (FAB L1, TdT+ to FAB M4, Auer rods, TdT-). In another patient, two distinct populations of myeloid and lymphoid blast cells were observed simultaneously (TdT-, LeuM1+/TdT+, LeuM1-). In two additional patients, acute leukemia was characterized by the expression of both lymphoid and myeloid markers on the same cell (TdT+/Leu M1+, B4+/Leu M1+ and greater than or equal to 70% TdT+, T11+, My9+). The Philadelphia (Ph1) chromosome was negative in all cases, though other chromosomal abnormalities were noted in three out of four cases. Malignant transformation of a pluripotential stem cell for both lymphoid and myeloid lineages, with or without the Ph1 chromosome marker, could explain the coexistence of distinct populations of lymphoblasts and myeloblasts in acute leukemia. Acute leukemia with a biphenotypic profile may reflect genome depression accompanying neoplasia.

scholarly journals Cytogenetic profile of minimally differentiated (FAB M0) acute myeloid leukemia: correlation with clinicobiologic findings [see comments]

Blood ◽  
1995 ◽  
Vol 85 (12) ◽  
pp. 3688-3694 ◽  
Author(s):  
A Cuneo ◽  
A Ferrant ◽  
JL Michaux ◽  
M Boogaerts ◽  
H Demuynck ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Normal Karyotype ◽  
Clinical Findings ◽  
Trisomy 13 ◽  
Professional Exposure ◽  
Cytogenetic Profile ◽  
Acute Myeloid ◽  
Clonal Abnormalities

Cytogenetic data were studied in 26 patients with de novo acute myeloid leukemia (AML) with minimal myeloid differentiation, corresponding to the M0 subtype of the French-American-British classification, in correlation with cytoimmunologic and clinical findings. Clonal abnormalities were detected in 21 cases (80.7%), 12 of which had a complex karyotype. Partial or total monosomy 5q and/or 7q was found, either as the sole aberration or in all abnormal metaphases, in 11 patients; in 8 cases, additional chromosome changes were present, including rearrangements involving 12p12–13 and 2p12–15 seen in 3 cases each. Five patients had trisomy 13 as a possible primary chromosome change; in 5 cases, nonrecurrent chromsome abnormalities were observed. Comparison of these findings with chromosome data from 42 patients with AML-M1 shows that abnormal karyotypes, complex karyotypes, unbalanced chromosome changes (-5/5q- and/or -7/7q- and +13) were observed much more frequently in AML-M0 than in AML-M1. Patients with abnormalities of chromosome 5 and/or 7 frequently showed trilineage myelodysplasia and low white blood cell count. Despite their relatively young age, complete remission was achieved in 4 of 11 patients only. Patients with +13 were elderly males with frequent professional exposure to myelotoxic agents. Unlike patients with clonal abnormalities, most AML-M0 patients with normal karyotype showed 1% to 2% peroxidase-positive blast cells at light microscopy and frequently achieved CR. It is concluded that (1) AML-M0 shows a distinct cytogenetic profile, partially recalling that of therapy-related AML, (2) different cytogenetic groups of AML-M0 can be identified showing characteristic clinicobiologic features, and (3) chromosome rearrangements may partially account for the unfavorable outcome frequently observed in these patients.

Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA)

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2717-2723 ◽  
Author(s):  
Claude Preudhomme ◽  
Christophe Sagot ◽  
Nicolas Boissel ◽  
Jean-Michel Cayuela ◽  
Isabelle Tigaud ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Prognosis Factor ◽  
Cebpa Mutations ◽  
Factor C ◽  
French Association ◽  
Acute Myeloid

The transcription factor C/EBPα is crucial for differentiation of mature granulocytes. Recently, differentCEBPA gene mutations likely to induce differentiation arrest have been described in nearly 10% of patients with acute myeloid leukemia (AML). In the present study, we retrospectively analyzed the prognostic significance of CEBPA mutations in 135 AML patients (French-American-British [FAB]-M3 excluded). All patients were prospectively enrolled between 1990 and 1996 in a multicenter trial of the ALFA (Acute Leukemia French Association) Group (median age 45 years, median follow-up 5.7 years). Mutations were assessed using direct sequencing of the CEBPA gene. Twenty-two mutations were found in 15 (11%) of 135 patients tested. Twelve patients had at least one mutation located in the N-terminal part of the protein leading to the lack of expression of the full-length C/EBPα protein. CEBPA mutations were present only in patients belonging to the intermediate cytogenetic risk subgroup and associated with the FAB-M1 subtype (P = .02). FLT3 internal tandem duplication (ITD) was found in 5 of 15 CEBPA-mutated as compared with 30 of 119 CEBPA-nonmutated cases tested (P = .54). Presence of CEBPA mutations was identified as an independent good prognosis factor for outcome even after adjustment on cytogenetics and FLT3 status (estimated 5-year overall survival 53% vs 25%, P = .04).FLT3-ITD appeared to act as a major bad prognosis factor in patients with CEBPA-mutated AML. We thus propose a risk classification that includes in the favorable subgroup all patients from the intermediate subgroup displaying CEBPA mutations when not associated with FLT3-ITD.

Phase I Study of Lenalidomide in Acute Leukemia: Remissions in Post-Allogeneic Relapse of Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 841-841 ◽  
Author(s):  
Jason C. Chandler ◽  
Rebecca B. Klisovic ◽  
Mitch A. Phelps ◽  
Alison Walker ◽  
Ramiro Garzon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Leukemia ◽  
Phase I ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Allogeneic Transplantation ◽  
Initial Therapy ◽  
Trisomy 13 ◽  
Acute Myeloid

Abstract Abstract 841 Lenalidomide is effective in myeloma and low-risk myelodysplastic syndromes (MDS), especially MDS with the 5q- cytogenetic abnormality, and may also have activity in acute leukemia. We designed a phase I dose escalation trial of lenalidomide in adults with relapsed or refractory acute leukemia to determine the maximum tolerable dose (MTD) and dose limiting toxicity (DLT), as well as to provide preliminary efficacy data in this setting. 35 adults with acute leukemia were enrolled: 31 with acute myeloid leukemia (AML) and 4 with acute lymphoblastic leukemia (ALL). Patients had a median age of 63 years (range, 22-79) and had received a median of 2 prior therapies (range, 1-4). 8 patients had relapsed after transplantation (7-allogeneic, 1-autologous). Patients were treated orally with lenalidomide on days 1-21 of 28 day cycles at the following dose levels: 25mg/day (N=4), 35mg/day (N=9), 50mg/day (N=19, including the expansion at the MTD), and 75mg/day (N=3). Patients were eligible to receive additional cycles of treatment beyond cycle 1 in the absence of disease progression defined as 25% increase in blasts relative to pretreatment. The median number of cycles received was 1 (range, 1-7). DLTs were assessed during cycle 1 of therapy. DLTs were sudden death (N=1, autopsy ruled out pulmonary embolism), rash (N=1), line-associated thrombosis (N=1), and fatigue (N=3). Grade 3 fatigue occurred in two patients at 75mg/day; 50mg/day was thus declared the recommended phase 2 dose and 10 additional patients were treated at this dose. The major toxicities associated with treatment were drug and disease associated myelosuppression and infection, as expected; these did not constitute DLT. In spite of concerns that higher dose lenalidomide would be associated with increased risk of thromboembolism, this toxicity was infrequent, even during multiple cycles of therapy. Two events occurred; both were line associated, and neither was life-threatening. Detailed pharmacokinetic results for the dose escalation cohorts in the trial are listed in the table below. Maximum plasma lenalidomide concentrations and area under the concentration-time curve (AUC) increased proportionally with dose. Drug clearance was independent of dose and correlated with calculated creatinine clearance. Of 31 patients with AML there were 5 complete responses (CR) (by IWG criteria for AML; Cheson, JCO 2003). 3/3 with cytogenetically abnormal AML achieved cytogenetic CR (cCR) as well. Achievement of CR was delayed beyond 2 months from initiation of therapy in each case. The duration of CR was 2.4-8.8 months, with two responders still in CR at 2.4+ and 4.7+ months, respectively. At 25mg, a 74 year old with AML in 2nd relapse with widespread leukemia cutis but no blood/marrow involvement had resolution of disease after 2 cycles. At 35mg, a 69 year old with AML and trisomy 13 achieved cCR after 2 cycles. At 50mg, there were three CRs, including two patients who received lenalidomide as initial therapy for relapsed AML following allogeneic stem cell transplant. In both of these cases, lenalidomide therapy was associated with the onset of skin rash requiring temporary discontinuation of drug; CR was achieved after 2 to 3 cycles of therapy and was preceded by cytogenetic remission before count recovery occurred. A third CR at the 50mg level occurred in a 70 year old with AML who had lenalidomide discontinued after 2 cycles due to no apparent response. Subsequently, CR was achieved 1 month later with no intervening therapy. In conclusion, single agent lenalidomide induced CR in 16% (5/31) of relapsed/ refractory AML patients. None of the responders had 5q-. The DLT was fatigue; the MTD was 50mg daily for days 1-21. Achievement of CR without donor leucocyte infusion in 2/4 patients who received lenalidomide as initial therapy for AML relapse following allogeneic transplantation suggests a possible allogeneic immunomodulatory effect. We are now developing a CTEP-sponsored study of lenalidomide as maintenance following allogeneic transplantation for AML. The promising single agent efficacy reported here supports further study of lenalidomide in combination with other agents in high risk AML. Disclosures: Blum: Celgene: Research Funding.

scholarly journals Early T cell differentiated chronic myeloid leukemia blast crisis with rearrangement of the breakpoint cluster region but not of the T cell receptor beta chain genes

Blood ◽  
1987 ◽  
Vol 69 (4) ◽  
pp. 1082-1086 ◽  
Author(s):  
M Gramatzki ◽  
CR Bartram ◽  
D Muller ◽  
M Walter ◽  
H Tittelbach ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
T Cell Receptor ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Cell Receptor ◽  
T Cell Differentiation ◽  
Beta Chain ◽  
T Cell Receptor Beta ◽  
Receptor Beta

Early T cell differentiation is described in a case of Philadelphia chromosome-positive chronic myeloid leukemia (CML) in blast crisis, supporting multi-lineage differentiation potential of CML precursor cells. In the absence of myeloid markers, strong positivity for terminal deoxynucleotidyl transferase (TdT) and reactivity with T cell antibody 3A1, but lack of more mature T cell antigens, provided evidence for immature T cell differentiation. Molecular analysis of the breakpoint cluster region (bcr) in chromosome 22 revealed a rearrangement and thus confirmed the CML origin of the early T cell blasts. T cell receptor beta chain sequences were found in germline configuration and therefore suggest a very immature stage of T cell differentiation in the CML blasts.

Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1308-1316 ◽  
Author(s):  
Frank Dicker ◽  
Claudia Haferlach ◽  
Wolfgang Kern ◽  
Torsten Haferlach ◽  
Susanne Schnittger
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
Fold Increase ◽  
Fusion Transcript ◽  
Trisomy 13 ◽  
Transcript Levels ◽  
High Incidence ◽  
Flt3 Mutations ◽  
Acute Myeloid

AbstractAML1/RUNX1 is implicated in leukemogenesis on the basis of the AML1-ETO fusion transcript as well as somatic mutations in its DNA-binding domain. Somatic mutations in RUNX1 are preferentially detected in acute myeloid leukemia (AML) M0, myeloid malignancies with acquired trisomy 21, and certain myelodysplastic syndrome (MDS) cases. By correlating the presence of RUNX1 mutations with cytogenetic and molecular aberration in a large cohort of AML M0 (N = 90) at diagnosis, we detected RUNX1 mutations in 46% of cases, with all trisomy 13 cases (n = 18) being affected. No mutations of NRAS or KIT were detected in the RUNX1-mutated group and FLT3 mutations were equally distributed between RUNX1-mutated and unmutated samples. Likewise, a high incidence of RUNX1 mutations (80%) was detected in cases with trisomy 13 from other French-American-British (FAB) subgroups (n = 20). As FLT3 is localized on chromosome 13, we hypothesized that RUNX1 mutations might cooperate with trisomy 13 in leukemogenesis by increasing FLT3 transcript levels. Quantitation of FLT3 transcript levels revealed a highly significant (P < .001) about 5-fold increase in AML with RUNX1 mutations and trisomy 13 compared with samples without trisomy 13. The results of the present study indicate that in the absence of FLT3 mutations, FLT3 overexpression might be a mechanism for FLT3 activation, which cooperates with RUNX1 mutations in leukemogenesis.

scholarly journals Gene Expression Profiling in the Classification of Acute Leukemia Brazilian Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5315-5315
Author(s):  
Carolina Pereira de Souza Melo ◽  
Catharina Brant Campos ◽  
Alvaro Pimenta Dutra ◽  
Angelo Atalla ◽  
Mara Albonei Dudeque Pianovski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Bioinformatic Analysis ◽  
Gene Signature ◽  
World Health ◽  
Prediction Algorithm ◽  
Lymphoid Leukemia ◽  
Number Of Patients

Abstract In the past few decades, genetic data has become increasingly important for acute leukemia diagnosis and patients stratification. Indeed, the present World Health Organization (WHO) leukemia classification system is largely based upon genetically defined subgroups. Gene expression profile (GEP) may correctly predict most genetic leukemia subtypes, but so far no GEP report has evaluate patients from Latin America. In the present study, we used gene expression microarray data to build an acute leukemia classifier. Bone marrow samples were collected from 231 individuals at diagnosis, 110 presented de novo acute myeloid leukemia (AML), 97 had de novo acute lymphoid leukemia (ALL) and the remaining 24 were controls who had other conditions including chronic leukemias or non-hematological diseases. GEP was evaluated based on mRNA expression signatures obtained with the Sure Print G3 Human GE (60k) system (Agilent Technologies). k-nearest neighbors prediction algorithm was applied and the top 60 informative genes were selected for each of the most prevalent genetic subtypes (T-ALL, B-ALL BCR-ABL, B-ALL ETV6-RUNX1, B-ALL TCF3-PBX1, AML PML-RARa, AML RUNX1-RUNX1T1, AML FLT3-ITD, AML NPM1mut). The less prevalent groups such as MLL rearranged and CBFB-MYH11 were not included in the classifier because of the low number of patients carrying these aberrations in our cohort. Performance of each prediction model was assessed by leave-one-out crossvalidation through the GenePattern platform (Broad Institute). The average classifier accuracy was 94.75%. Higher accuracy and precision were achieved for T-ALL (99%/96%) and AML PML-RARa (97%/97%). However, for ALL BCR-ABL, AML FLT3-DIT and AML NPM1mut the gene signature had low precision rates (74%, 66% and 80%, respectively). The data presented here confirm that a single platform of gene expression followed by bioinformatic analysis can correctly classify genetic subgroups, but a refinement of the classifier developed is needed in order to improve the detection of heterogeneous entities such as BCR-ABL or FLT3-ITD carriers. Disclosures No relevant conflicts of interest to declare.

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