scholarly journals Isochromosome der(17)(q10)t(15;17) in acute promyelocytic leukemia resulting in an additional copy of the RARA-PML and loss of one p53 gene: Report of two cases and literature review

2019 ◽  
Vol 76 (9) ◽  
pp. 960-967
Author(s):  
Vesna Djordjevic ◽  
Marija Dencic-Fekete ◽  
Jelica Jovanovic ◽  
Marijana Virijevic ◽  
Nada Kraguljac-Kurtovic ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Acute Promyelocytic Leukemia ◽  
P53 Gene ◽  
Promyelocytic Leukemia ◽  
Chromosome 17 ◽  
Gene Copy ◽  
Fish Analysis ◽  
Derivative Chromosome ◽  
Tumor Suppressor P53 ◽  
Poor Prognostic Factor

Introduction. The isochromosome of the long arm of derivative chromosome 17, that originates from the translocation t(15;17) [ider(17)(q10)t(15;17), or ider(17q)] in acute promyelocytic leukemia (APL), is a rare chromosome aberration associated with a poor prognosis. Case report. We report the clinical and laboratory data associated with ider(17q) for two APL patients. Cytogenetic analysis of bone marrow cells in both cases showed a mosaic karyotype with the ider(17q); reverse transcription polymerase chain reaction (RT-PCR) was positive for the long (L) isoform of the retionic acid receptor alpha (PML-RARA) fusion transcript in each patient. Fluorescence in situ hybridization (FISH) analysis with the DNA probes for the PML gene on 15q24.1, and the RARA gene on 17q21.2, confirmed the extra copy of the RARA-PML fusion gene or ider(17q). Additionally, the FISH analysis with a DNA probe for the p53 gene on 17p13.1 confirmed loss of one copy of the universal tumor suppressor p53 in both patients. Conclusion. Both reported APL patients with ider(17q) had predominance of the clone with ider(17q) compared to those with t(15;17) and/or the normal karyotype, indicating that duplication of der(17) may provide a growth advantage allowing the relevant clone to become dominant. Moreover, as an important oncogenic event and poor prognostic factor in leukemia, loss of one gene copy of the tumor suppressor p53, may also contribute to this growth advantage. Although the clinical and prognostic significance for the patients with an ider(17q) remains unclear, cytogenetic and molecular-genetic analysis should be combined to reveal more details about this complex and rare chromosomal abnormality.

A Novel t(3;17) Variant of Acute Promyelocytic Leukemia with Rearrangement of the RARA Locus.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4428-4428
Author(s):  
Robert L. Redner ◽  
Lydia C. Contis ◽  
Carol Evans ◽  
Maureen E. Sherer ◽  
Sofia Shekhter-Levin
Keyword(s):  
Bone Marrow ◽  
Acute Promyelocytic Leukemia ◽  
Bone Marrow Cells ◽  
Flow Cytometric Analysis ◽  
Control Culture ◽  
Promyelocytic Leukemia ◽  
Dna Probe ◽  
Chromosome 17 ◽  
Fish Analysis ◽  
Dual Color

Abstract The vast majority of patients with Acute Promyelocytic Leukemia (APL, FAB M3) have the t(15;17)(q12;q21) chromosomal translocation. This introduces the gene for PML into the retinoic acid receptor alpha (RARA) locus, which leads to expression of a PML-RARA fusion. There is convincing evidence that expression of PML-RARA underlies the APL phenotype. Yet, there have been identified rare cases of APL that do not manifest t(15;17). Many of these cases exhibit cryptic rearrangements of PML and RARA. However, in a number of cases it has clearly been shown that a fusion protein different than PML-RARA is expressed. These include the t(11;17)(q23;q21) that expresses a PLZF-RARA fusion; t(5;17)(q35;q21) that encodes NPM-RARA; t(11;17)(q13;q21) that encodes NUMA-RARA; and der(17) with duplication of 17q21.3-q23 that fuses STAT5b to RARA. We report here a novel case of APL with t(3;17) with rearrangement of RARA, but not PML. A 72 year old man presented with leukocytosis, anemia, and thrombocytopenia: wbc 20.4 X10E+9/L; hgb 10.3 g/L; PLT 22 x10E+9/L. The wbc differential showed 20% polys, 4% bands, 15% lymphocytes, 19% monocytes, 34% blasts, 1% promyelocyte, 6% myelocyte, 1% metamyelocytes. Auer rods were seen. The bone marrow was hypercellular (approximately 80%), with 88% blasts, 1.7% promyelocytes, 0.3% myelocyte, 0.3% polys, 0.3% eosinophile, 3% monocytes, 0.3% pronormoblasts, 3.7% normoblasts, and 2.3% lymphocytes. The blasts demonstrated prominent cytoplasmic granulation, Flow cytometric analysis showed the blasts to be CD117 positive, myeloperoxidase positive, CD13/33 positive, but lacking CD34 or HLA-DR expression, consistent with a diagnosis of APL. Cytogenetic studies indicated a mosaic abnormal analysis with an apparent normal cell line and one that demonstrated a 47,XY,t(3;17)(p25;q12-21), +8 karyotype. Analysis for PML-RARA expression by RT-PCR was indeterminate, owing to poor quality of the extracted RNA. Fluorescence In Situ Hybridization (FISH) was therefore performed on two hundred unstimulated cells, primarily in interphase, using the Vysis t(15;17) dual color DNA probe. 98.5% of the cells were negative for PML-RARA rearrangement (the value of 1.5% positivity is within the laboratory’s control range for false positives). To confirm that the t(3;17) rearrangement involved the RARA locus, we scored 203 unstimulated cells using the LSI RARA dual color DNA probe. 100% were positive for the RARA gene rearrangement (split signal). Four metaphase cells each showed one fused red/green signal on the normal chromosome 17, one red signal on der (17), and one green signal on the distal arm of chromsome 3. The FISH analysis therefore indicated rearrangement of the RARA, but not the PML locus. The patient expired before treatment could begin. To determine whether the t(3;17) blasts could differentiate (a hallmark of t(15;17) APL), we cultured the bone marrow cells in RPMI 1640 with 10% FCS and 10E-6 M ATRA. At 10 days 58% of the cells resembled metamyelocytes, bands, or mature polys, compared with none in the control culture. This indicates that t(3;17) retains its ability to differentiate in the presence of ATRA, consistent with its classification as a novel variant of APL.

Coexpression of PML/RARα and AML1/ETO Leads to ATRA Resistance In Vivo in Acute Promyelocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4273-4273
Author(s):  
Rodrigo S. Abreu e Lima ◽  
Marcelo R. Baruffi ◽  
Ana Silvia G. Lima ◽  
Lorena L. Figueiredo ◽  
Roberto P. Falcao ◽  
...  
Keyword(s):  
Southern Blot ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Immunofluorescence Staining ◽  
Leukemic Cells ◽  
Chromosome 17 ◽  
Fish Analysis ◽  
Rt Pcr ◽  
Hla Dr

Abstract Acute promyelocytic leukemia (APL) associated with the t(15;17)/PML/RARα and AML with t(8;21)/AML1/ETO are AML subtypes characterized by distinct cytomorphological and clinical features. The coexistence of both genetic abnormalities in a single leukemic clone is extremely rare, and whether it affects PML subcellular distribution or the response to the treatment with all trans retinoic acid (ATRA) has not been previously analyzed. Here we report an AML case refractory to treatment in which the PML/RARα or AML1/ETO expression was analyzed by conventional cytogenetics, FISH, RT-PCR, Southern blot and Spectral Karyotyping (SKY), in addition PML distribution was analyzed by immunofluorescence staining. A 47-year-old female patient complaining of dyspnea for 1 month and presenting hematomas and pallor was referred to the University Hospital of Ribeirao Preto. Adenopathy and splenomegaly were absent. The hemoglobin level was 6g/dl, platelet count was 14x103/ml and leukocyte count was 10.2x103/ml with 22% blasts. The coagulation profile was normal, except for the D-dimers level wich was between 4,000 – 8,000 ng/ml. The differential counts of bone marrow (B.M.) aspirates revealed the presence of 21% blasts and 24% promyelocytes. Immunofluorescence staining of B.M. cytospin preparations using the PG-M3 antibody revealed that PML was delocalizated from the nuclear bodies, a feature suggestive of the diagnosis of APL. The immunophenotypic analysis identified two cell subsets: one CD33+ CD13+ HLA-DR− CD34− CD15+ with high Sideward Scatter (SSC) and another one CD33+ CD13+ HLA-DR+ CD34+ CD15− with low SSC values. The karyotype after G-banding was as follows: 46X, iso(X)(q11), t(8;21)(q22;q12) in 18/18 metaphases.SKY analysis confirmed the chromosomal abnormalities detected by G-banding and identified a cryptic insertion of chromosome 15 material into chromosome 17 in 5/5 metaphases.The expression of AML1/ETO and PML/RARα genes was demonstrated by RT-PCR. FISH analysis were performed using Vysis PML and RARα probes did not detect PML/RARα rearrangements in 300 interphases. On the contrary, FISH assays using Vysis AML1and ETO probes confirmed the presence of t(8;21) in 15% of 300 interphases. Finally, RARα rearrangement was detected by Southern blot analysis performed on B.M. cells genomic DNA using the H18 and K3 RARα genomic probes.The patient was treated with ATRA 45 mg/m2/d for 30 days associated with standard 3+7 AML induction regimen but did not achieve remission. ATRA dose was increased to 90 mg/m2/d and a second identical course of chemotherapy was administered from Day +35. B.M. aspirate obtained on Day +63 presented 2% of blasts/promyelocytes, but the PML/RARαand AML1/ETO transcripts were still detectable by RT-PCR. The patient died of sepsis on Day +67. The lack of response to ATRA observed in this patient contrasts with the favorable outcome observed in the majority of APL patients.Since both PML/RARα and AML1/ETO oncoproteins affect transcription by forming repressor complexes containing histone deacetylase, it is formally possible that their coexpression could lead to irreversible chromatin remodeling. Despite its rarity, the present case is informative because it suggests that PML/RARα and AML1/ETO may synergize and thus render the leukemic cells resistant to treatment.

Acute promyelocytic leukemia with submicroscopic deletion of 3′-region ofPMLon derivative chromosome 17

2008 ◽  
Vol 49 (11) ◽  
pp. 2213-2215
Author(s):  
Junsook Ha ◽  
Dohoon Kim ◽  
Jihae Kim ◽  
Wonmok Lee ◽  
Namhee Ryoo ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Chromosome 17 ◽  
Derivative Chromosome ◽  
Submicroscopic Deletion

Loss of the Tumor Suppressor p53 Gene at the Liver Cirrhosis Stage in Japanese Patients with Hepatocellular Carcinoma

Oncology ◽  
1997 ◽  
Vol 54 (4) ◽  
pp. 304-310 ◽  
Author(s):  
Yosuke Kishimoto ◽  
Goshi Shiota ◽  
Yoshinori Kamisaki ◽  
Kouichirou Wada ◽  
Kentaro Nakamoto ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Tumor Suppressor ◽  
P53 Gene ◽  
Japanese Patients ◽  
Tumor Suppressor P53

scholarly journals Localization of the G-CSF gene on chromosome 17 proximal to the breakpoint in the t(15;17) in acute promyelocytic leukemia

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 330-332
Author(s):  
RN Simmers ◽  
LM Webber ◽  
MF Shannon ◽  
OM Garson ◽  
G Wong ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Regulatory Region ◽  
Chromosome Translocation ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Chromosome 17 ◽  
Granulocyte Colony Stimulating Factor ◽  
Coding Region ◽  
Stimulating Factor

The human granulocyte-colony stimulating factor gene (G-CSF) is localized at 17q11.2-q21, the region of one of the breakpoints in the 15;17 chromosome translocation specific for acute promyelocytic leukemia (APL). As G-CSF induces differentiation and loss of tumorigenicity in myeloid leukemic cells or cell lines, it was possible that the translocation in APL involved the DNA of the G-CSF coding region or its regulatory region. In situ hybridization to chromosomes with the t(15;17) from patients with the APL translocation using a G- CSF cDNA clone revealed that the coding region of this gene is proximal to the t(15;17) breakpoint on chromosome 17. Southern analysis of DNA from patients with the APL translocation showed no differences in hybridization between normal and leukemic cells. These results indicate that the G-CSF coding sequence is not disrupted by the chromosomal rearrangement characteristic of APL.

scholarly journals Hyperbasophilic Variant of Acute Promyelocytic Leukemia

2016 ◽  
Vol 3 (2) ◽  
pp. 125
Author(s):  
Preeti Bajaj ◽  
Rajyaguru Devangana ◽  
B. S. Shah ◽  
Amrinder Kaur
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Genetic ◽  
Chromosomal Translocation ◽  
Promyelocytic Leukemia ◽  
Chromosome 17 ◽  
Chromosome 15 ◽  
Chromosome 11 ◽  
Acute Myeloid

Acute Promyelocytic Leukemia (APL) is an extremely rare variant of acute myeloid leukemia. APL constitutes around 10-15 % of acute myeloid leukemia in adults. It is commonly diagnosed around 40 years age. Molecular/genetic studies exhibit chromosomal translocation between chromosome 15 and chromosome 17-t(15;17)(q22;q21) and PML-RARa rearrangement. Four variants of APL have been identified: The classic form M<sub>3</sub> hypergranular variant, the microgranular variant, the hyperbasophilic form and zinc-finger form-M<sub>3</sub>r, identified by a different chromosomal translocation, between chromosome 11 and chromosome 17:t(11,17) (q23, q11-12).

Sign in / Sign up

Export Citation Format

Share Document