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![Karyotype and FISH analysis. a Karyogram of patient#13. Karyotype: 46,XY,t(11;16)(q23;p13)[20]. b FISH analysis using a KTM2A dual-color break-apart rearrangement probe which hybridizes to band 11q23 (spectrum green on the centromeric side and spectrum red on the telomeric side of the KTM2A gene breakpoint) shows a split red-green signal, indicating KTM2A rearrangement](publication/338953994/figure/fig3/AS:960057818763275@1605907029284/Karyotype-and-FISH-analysis-a-Karyogram-of-patient13-Karyotype.png)
Karyotype and FISH analysis. a Karyogram of patient#13. Karyotype: 46,XY,t(11;16)(q23;p13)[20]. b FISH analysis using a KTM2A dual-color break-apart rearrangement probe which hybridizes to band 11q23 (spectrum green on the centromeric side and spectrum red on the telomeric side of the KTM2A gene breakpoint) shows a split red-green signal, indicating KTM2A rearrangement
Source publication
Fusion partners of KMT2A affect disease phenotype and influence the current World Health Organization classification of hematologic neoplasms. The t(11;16)(q23;p13)/KMT2A-CREBBP is considered presumptive evidence of a myelodysplastic syndrome (MDS) and a MDS-related cytogenetic abnormality in the classification of acute myeloid leukemia (AML). Here...
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Citations
... Translocation Partner References t(8;21)(q22;q22) ETO (RUNX1T1) [13,14,[19][20][21] AML1 (RUNX1) t(3;21)(q26.2;q22) MDS1-EVI1 (MECOM, PRDM3) [22,23] t(1;21)(p36;q21) PRDM16 [24,25] t(9;11)(p22;q23) AF9 (MLLT3) [14,20] [20,28,29] t(11;16)(q23;p13) CREBBP [30][31][32] It is worth noting that this set of translocations differs from the recurrent translocations in other types of t-AML, such as those induced by alkylating agents or radiotherapy [10,19]. Therefore, the manner in which the DSBs are introduced plays a significant role in the formation of translocations. ...
Topoisomerase inhibitors are widely used in cancer chemotherapy. However, one of the potential long-term adverse effects of such therapy is acute leukemia. A key feature of such therapy-induced acute myeloid leukemia (t-AML) is recurrent chromosomal translocations involving AML1 (RUNX1) or MLL (KMT2A) genes. The formation of chromosomal translocation depends on the spatial proximity of translocation partners and the mobility of the DNA ends. It is unclear which of these two factors might be decisive for recurrent t-AML translocations. Here, we used fluorescence in situ hybridization (FISH) and chromosome conformation capture followed by sequencing (4C-seq) to investigate double-strand DNA break formation and the mobility of broken ends upon etoposide treatment, as well as contacts between translocation partner genes. We detected the separation of the parts of the broken AML1 gene, as well as the increased mobility of these separated parts. 4C-seq analysis showed no evident contacts of AML1 and MLL with loci, implicated in recurrent t-AML translocations, either before or after etoposide treatment. We suggest that separation of the break ends and their increased non-targeted mobility—but not spatial predisposition of the rearrangement partners—plays a major role in the formation of these translocations.
... On the other hand, the CBP gene encodes a transcriptional adaptor/coactivator protein in the 16p13 locus, and is involved in the regulation of the cell cycle [69]. It was postulated that one possible explanation for the leukemogenesis of t(11;16)-positive MDS is the loss of function in CBP to regulate the cell cycle by its structural alteration when fused with KMT2A [70]. The OS of adult patients with t(11;16) in one study was similar to adult patients with therapy-related myeloid neoplasms and complex karyotypes [70]. ...
... It was postulated that one possible explanation for the leukemogenesis of t(11;16)-positive MDS is the loss of function in CBP to regulate the cell cycle by its structural alteration when fused with KMT2A [70]. The OS of adult patients with t(11;16) in one study was similar to adult patients with therapy-related myeloid neoplasms and complex karyotypes [70]. (3)) and balance translocation of chromosome 3 (t(3;3)) are observed in approximately 1% of the cases, and has been categorized in the poor prognostic subgroup [6]. ...
Myelodysplastic syndromes (MDS) are heterogeneous groups of clonal myeloid disorders characterized by unexplained persistent peripheral blood (PB) cytopenia(s) of one or more of the hematopoietic lineages, or bone marrow (BM) morphologic dysplasia in hematopoietic cells, recurrent genetic abnormalities, and an increased risk of progression to acute myeloid leukemia (AML). In the past several years, diagnostic, prognostic, and therapeutic approaches have substantially improved with the development of Next Generation Sequencing (NGS) diagnostic testing and new medications. However, there is no single diagnostic parameter specific for MDS, and correlations with clinical information, and laboratory test findings are needed to reach the diagnosis.
Leukemia is a blood cancer that originates in the blood and bone marrow. Therapy-related leukemia is a leukemia associated with prior chemotherapy. Cancer therapy with DNA-topoisomerase II inhibitors is one of the most effective among chemotherapies. However, its side effect can be the development of secondary leukemia, characterized by chromosomal rearrangements involving the AML1 or MLL gene. The set of recurrent translocations in such leukemia differs from the set of chromosomal rearrangements in other neoplasia. We review the factors that drive the translocations upon treatment of cells with DNA-topoisomerase inhibitors. Such factors primarily include the mobility of double-strand DNA ends prior to translocation and the gain of functions of the fusion proteins that are formed in the cell as a result of translocation.
Leukemia is a blood cancer originating in the blood and bone marrow. Therapy-related leukemia is associated with prior chemotherapy. Although cancer therapy with DNA topoisomerase II inhibitors is one of the most effective cancer treatments, its side effects include development of secondary leukemia characterized by the chromosomal rearrangements affecting AML1 or MLL genes. Recurrent chromosomal translocations in the therapy-related leukemia differ from chromosomal rearrangements associated with other neoplasias. Here, we reviewed the factors that drive chromosomal translocations induced by cancer treatment with DNA topoisomerase II inhibitors, such as mobility of ends of double-strand DNA breaks formed before the translocation and gain of function of fusion proteins generated as a result of translocation.
Background
Acute myeloid leukemia (AML) with KMT2A (MLL) rearrangement is known for monocytic or myelomonocytic differentiation, but the full immunophenotypic spectrum and dynamic changes of the immunophenotype in this genetically defined disease have not been systematically studied.
Methods
We reviewed the immunophenotype, karyotype, and mutations at the time of initial diagnosis and relapse of adults with AML with KMT2A rearrangement in our institution between 2007 and 2020.
Results
We identified 102 patients: 44 men and 58 women with a median age of 52 years (range, 18–87). Forty-three patients were considered to be therapy-related. Twenty-four out of 64 patients relapsed from complete remission after induction therapy, 34 had persistent/progressive disease, and 58 patients died with a median overall survival of 17 months.
We detected five immunophenotypes: immature monocytic (38%); myelomonocytic (22%); myeloblastic (22%); mature monocytic (10%); and acute promyelocytic (APL)-like (8%). By chromosomal breakpoints, we presumed 11 different partners; t(9;11) (p22;q23)/MLLT3-KMT2A was the most common rearrangement (n = 56, 55%), followed by t(6;11) (q27;q23)/AFDN-KMT2A (n = 13,13%). Patients with t(6;11) (q27;q23)/AFDN-KMT2A preferentially showed a myeloblastic phenotype (p = 0.026). Mutations were detected in 39/64 (61%) cases, and RAS pathway (NRAS/KRAS/PTPN11) was involved in 26/64 (41%) cases. None of the APL-like cases had mutations detected. At the time of disease relapse, 10/24 (42%) showed major immunophenotypic change, and 7/10 cases gained additional cytogenetic and/or molecular alterations.
Conclusion
The immunophenotype of AML with KMT2A rearrangement is more diverse than previously recognized, with a substantial subset showing no evidence of monocytic differentiation. Major immunophenotype change is common at the time of relapse.
