Rare congenital aneuploid conditions such as trisomy 13, trisomy 18, trisomy 21 and Klinefelter syndrome (KS, 47,XXY) are associated with higher susceptibility to developing cancer compared with ...euploid genomes. Aneuploidy frequently co-exists with chromosomal instability, which can be viewed as a "vicious cycle" where aneuploidy potentiates chromosomal instability, leading to further karyotype diversity, and in turn, paving the adaptive evolution of cancer. However, the relationship between congenital aneuploidy
and tumor initiation and/or progression is not well understood. We used G-banding analysis, array comparative genomic hybridization analysis and quantitative fluorescence in situ hybridization for telomere length analysis to characterize the leukemic blasts of a three-year-old boy with KS and B-cell acute lymphoblastic leukemia (B-ALL), to gain insight into genomic evolution mechanisms in congenital aneuploidy and leukemic development. We found chromosomal instability and a significant reduction in telomere length in leukemic blasts when compared with the non-leukemic aneuploid cells. Reviewing published cases with KS and B-ALL revealed 20 additional cases with B-ALL diagnostic cytogenetics. Including our present case, 67.7% (14/21) had acquired two or more additional chromosomal aberrations at B-ALL diagnosis. The presented data indicate that congenital aneuploidy in B-ALL might be associated with chromosomal instability, which may be fueled by enhanced telomere attrition.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
: Polycythemia vera (PV) is a clonal myeloid stem cell disease characterized by a growth-factor independent erythroid proliferation with an inherent tendency to transform into overt acute myeloid ...malignancy. Approximately 95% of the PV patients harbor the
V617F mutation while less than 35% of the patients harbor cytogenetic abnormalities at the time of diagnosis.
Here we present a
V617F positive PV patient where G-banding revealed an apparently balanced t(2;4)(q35;q21), which was confirmed by 24-color karyotyping. Oligonucleotide array-based Comparative Genomic Hybridization (aCGH) analysis revealed an interstitial 5.4 Mb large deletion at 4q23q24. Locus-specific fluorescent in situ hybridization (FISH) analyses confirmed the mono-allelic 4q deletion and that it was located on der(4)t(2;4). Additional locus-specific bacterial artificial chromosome (BAC) probes and mBanding refined the breakpoint on chromosome 2. With these methods the karyotype was revised to 46,XX,t(2;4)(q36.1;q24)18/46,XX7.
: This is the first report on a PV patient associated with an acquired novel t(2;4)(q36.1;q24) and a concurrent submicroscopic deletion del(4)(q23q24). The study also underscores the benefit of combined usage of FISH and oligo-based aCGH analysis in characterizing chromosomal abnormalities. The present findings provide additional clues to unravel important molecular pathways in PV to obtain the full spectrum of acquired chromosomal and genomic aberrations, which eventually may improve treatment options.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Aneuploidy, the presence of an abnormal number of chromosomes in a cell, is one of the most obvious differences between normal and cancer cells. There is, however, debate on how aneuploid cells arise ...and whether or not they are a cause or a consequence of tumorigenesis. Further, it is important to distinguish aneuploidy (the "state" of the karyotype) from chromosomal instability (CIN; the "rate" of karyotypic change). Although CIN leads to aneuploidy, not all aneuploid cells exhibit CIN. One proposed route to aneuploid cells is through an unstable tetraploid intermediate because tetraploidy promotes chromosomal aberrations and tumorigenesis. Tetraploidy or near-tetraploidy (T/NT) (81-103 chromosomes) karyotypes with or without additional structural abnormalities have been reported in acute leukemia, T-cell and B-cell lymphomas, and solid tumors. In solid tumors it has been shown that tetraploidization can occur in response to loss of telomere protection in the early stages of tumorigenesis in colon cancer, Barrett's esophagus, and breast and cervical cancers. In hematological malignancies T/NT karyotypes are rare and the role of telomere dysfunction for the induction of tetraploidization is less well characterized. To further our understanding of possible telomere dysfunction as a mechanism for tetrapolydization in hematological cancers we here characterized the chromosomal complement and measured the telomere content by interphase nuclei quantitative fluorescence in situ hybridization (iQFISH) in seven hematological cancer patients with T/NT karyotypes, and after cytogenetic remission. The patients were identified after a search in our local cytogenetic registry in the 5-year period between June 2012 and May 2017 among more than 12,000 analyzed adult patients in this period. One advantage of measuring telomere content by iQFISH is that it is a single-cell analysis so that the telomere content can be distinguished between normal karyotype cells and cells with T/NT karyotypes. We find that the telomeres are particularly short in cells with T/NT karyotypes as compared with normal cells, and in T/NT karyotypes harboring additional chromosomal aberrations as well. These findings suggest that telomere dysfunction in hematological malignancies may be a mechanism for tetraploidization and CIN.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute ...myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained by differences in karyotype and/or age.
In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified by age and karyotype. Results were given crude and adjusted with 95% CIs.
Overall, frequencies of sAML and tAML were 19.8% and 6.6%, respectively. sAML, but not tAML, was associated with low likelihood of receiving intensive treatment. Among intensive therapy patients (n = 1,567), antecedent myeloid disorder or prior cytotoxic exposure was associated with decreased complete remission rates and inferior survival (3-year adjusted RR for MDS-sAML, non-MDS-sAML, and tAML: RR, 1.14; 95% CI, 1.02 to 1.32; RR, 1.27; 95% CI, 1.16 to 1.34; and RR, 1.16; 95% CI, 1.03 to 1.32, respectively) compared with de novo AML. Among patients ≥ 60 years old and patients with adverse karyotype, previous MDS or tAML did not impact overall outcomes, whereas non-MDS-sAML was associated with inferior survival across age and cytogenetic risk groups (adverse risk cytogenetics: 1-year adjusted RR, 1.47; 95% CI, 1.23 to 1.76; patients ≥ 60 years old: 1-year adjusted RR, 1.31; 95% CI, 1.06 to 1.61).
Our results support that de novo AML, sAML, and tAML are biologically and prognostically distinct subtypes of AML. Patients with non-MDS-sAML have dismal outcomes, independent of age and cytogenetics. Previous myeloid disorder, age, and cytogenetics are crucial determinants of outcomes and should be integrated in treatment recommendations for these patients.
A jumping translocation (JT) involves a single donor chromosome and two or more recipient chromosomes in which a similar chromosomal region is translocated to various recipient chromosomes in ...different cell lines of a single individual. JTs are often associated with telomeric regions. Only 21 acquired JTs have previously been described in myeloid malignancies. Three of these cases involved the 3q13.31-qter region of which all were associated with a dismal outcome. In our recent publication, “Characterization of an acquired jumping translocation involving 3q13.31-qter in a patient with de novo acute monocytic leukemia” 1, we characterized the breakpoint region 3q13.31 by oligo-based array comparative genomic hybridization analysis. The present article provides data on copy number aberrations observed in the subtelomeric regions of this patient. Copy number alterations in the subtelomeric region have not been addressed previously in patients with JT.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The t(12;21)(p13;q22), leading to ETV6/RUNX1 fusion, is of importance for leukemogenesis in acute lymphoblastic leukemia but is not sufficient for the leukemic transformation. Acquired secondary ...chromosomal aberrations are necessary for overt leukemia but their complete nature and genes involved are still elusive. In our recent publication, “Oligo-based aCGH analysis reveals cryptic unbalanced der(6)t(X;6) in pediatric t(12;21)-positive acute lymphoblastic leukemia”, we identified acquired common concurrent regions with 6q deletion and Xq duplication E. Kjeldsen (2016) 1. The present article provides data on genes that are associated with hematological malignancy and other cancers located in these common regions of chromosomal aberrations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The deregulation of miRNAs has been associated with several different cancer types. Deregulation occurs in several ways, but generally little is known about the basis for the distorted expression of ...miRNAs. We investigated the relation between copy number status and miRNA expression at the genome-wide level using cytogenetic and array-based methods to characterize genomic aberrations in hematopoietic cell lines. For the same cell lines, we obtained global miRNA expression profiles, and analyzed the genome-wide correlation using the Spearman's rank test. This analysis showed that the expression of only a two miRNAs (miR-324-5p encoded by MIR324 at 17p13.1 and miR-660 encoded by MIR660 at Xp11.23) was influenced by copy number status. Our data imply that no direct relation between copy number status and miRNA expression exists in the investigated cell lines.
•Five hematopoietic cell lines were characterized using microarray technologies•This provided global copy number status and miRNA expression profiles•The genome-wide correlation between these profiles was analyzed•We found that few miRNA's expression showed correlation to copy number•We conclude that little correlation exists between copy number and miRNA expression
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Most patients cannot be included in randomized clinical trials. We report real-world outcomes of all Danish patients with multiple myeloma (MM) treated with daratumumab-based regimens until 1 January ...2019. Methods Information of 635 patients treated with daratumumab was collected retrospectively and included lines of therapy (LOT), hematologic responses according to the International Myeloma Working Group recommendations, time to next treatment (TNT) and the cause of discontinuation of treatment. Baseline characteristics were acquired from the validated Danish Multiple Myeloma Registry (DMMR). Results Daratumumab was administrated as monotherapy (Da-mono) in 27.7%, in combination with immunomodulatory drugs (Da-IMiD) in 57.3%, in combination with proteasome inhibitors (Da-PI) in 11.2% and in other combinations (Da-other) in 3.8% of patients. The median number of lines of therapy given before daratumumab was 5 for Da-mono, 3 for Da-IMiD, 4 for Da-PI, and 2 for Da-other. In Da-mono, overall response rate (ORR) was 44.9% and median time to next treatment (mTNT) was 4.9 months. In Da-IMiD, ORR was 80.5%, and mTNT was 16.1 months. In Da-PI, OOR was 60.6% and mTNT was 5.3 months. In patients treated with Da-other, OOR was 54,2% and mTNT was 5.6 months. The use of daratumumab in early LOT was associated with longer TNT (p<0.0001). Patients with amplification 1q had outcome comparable to standard risk patients, while patients with t(4;14), t(14;16) or del17p had worse outcome (p = 0.0001). Multivariate analysis indicated that timing of treatment (timing of daratumumab in the sequence of all LOT that the patients received throughout the course of their disease) was the most important factor for outcome (p<0.0001). Conclusion The real-world outcomes of multiple myeloma patients treated with daratumumab are worse than the results of clinical trials. Outcomes achieved with daratumumab were best when daratumumab was used in combination with IMIDs and in early LOT. Patients with high-risk CA had worse outcomes, but patients with amp1q had similar outcomes to standard-risk patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Targeted therapy directed against rare disease‐propagating leukaemic stem cells (LSCs) is a promising prospect for improving the outcome of acute myeloid leukaemia (AML) patients. Thus, ...distinguishing LSCs from normal haematopoietic stem and progenitor cells (HSPCs) is essential. The CLEC12A receptor has been proposed as a specific marker of LSCs, and consequently as an appealing treatment target. To explore the role of CLEC12A in further detail, we investigated whether a sorting strategy based on the activity of aldehyde dehydrogenase and CLEC12A expression could separate residual normal HSPCs from LSCs in bone marrow from 5 AML patients. We demonstrate that this distinction was possible in 2/5 cases, however with evidence of pre‐leukaemic mutations in the CLEC12A‐ stem cells in one case. In contrast, cytogenetic and/or molecular aberrations were detected in both the CLEC12A+/− cell subsets in 3/5 AML cases studied. Furthermore, targeted next generation sequencing (NGS) of the sorted cell subsets revealed a pronounced clonal heterogeneity in the CLEC12A‐ cells suggestive of the leukaemia often originating in this immature cell subset. In conclusion, we provide proof‐of‐concept that precision diagnostics employing targeted cytogenetic/NGS‐based analyses on highly purified cell subsets could be a powerful tool for selecting patients eligible for LSC‐directed therapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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