Double minute chromosomes in acute myeloid leukemia and myelodysplastic syndrome: Identification of new amplification regions by fluorescence in situ hybridization and spectral karyotyping

Abstract

Double minute chromosomes (dmin) are small chromatin bodies consisting of genes amplified in an extrachromosomal location. dmins are uncommon in hematologic malignancies; they are seen primarily in acute myeloid leukemia, with amplification of the MYC oncogene or, less frequently, the MLL transcription factor. Nine patients with hematologic malignancies with dmin were seen at the Roswell Park Cancer Institute between 1985 and 2000; eight had acute myeloid leukemia and one a myelodysplastic syndrome. Fluorescence in situ hybridization (FISH) demonstrated MYC amplification on dmin in four patients, but MLL amplification was not seen. Spectral karyotyping showed that the dmin derived from chromosome 11 in one patient and from chromosome 19 in two others without MYC or MLL amplification; derivation from these chromosomes was confirmed by FISH with chromosome paint probes. The dmin of chromosome 11 origin hybridized to a bacterial artificial chromosome (BAC) RP11-112M22 that maps to 11q24.3 and is predicted to contain ETS1 and other markers, including D11S11351 and D11S4091. The dmin of chromosome 19 origin in one patient hybridized to BACs RP11-46I12 and RP11-110J19; in the other patient, these clones did not hybridize with the dmin, but were found to be amplified on a marker chromosome that was derived from chromosome 19 in that patient's cells. These BACs have been mapped to 19q12-19q13.1 and 19q11-19q13.1, respectively, and are predicted to contain the markers D19S409 and D19S919 and the gene for ubiquinol-cytochrome C reductase, Rieske iron-sulfur polypeptide1 (UQCRFS1). dmin originating from chromosome 19 have not been reported previously in hematologic malignancies.

Amplification of the ABL gene in T-cell acute lymphoblastic leukemia

“…FISH studies have revealed the genes involved in the amplified regions. Amplifications of the MYC and MLL genes have been previously reported in acute myeloid leukemia (AML), [2][3][4] and of AML1 and MLL in ALL. 3,5 Although amplification of the BCR/ABL fusion gene has been described in cases of chronic myeloid leukemia (CML) treated with imatinib mesylate, seen both as HSRs 6 and dmins, 7 amplification of ABL alone is rare.…”

“…3 Finally, multiple studies show statistically significant reductions in relapse rates in patients who develop acute GVHD, chronic GVHD or both. 4 Unfortunately, the efficacy of a GVL effect in the context of DLI for ALL relapse post-transplant is quite unimpressive. One…”

BLIMP1α, the master regulator of plasma cell differentiation is a tumor supressor gene in B cell lymphomas

“…Deleterious mutations of PRDM1 associated with loss of BLIMP1 protein have also been reported in primary central nervous system lymphoma 63 . Finally, ETS-1, the transcription factor, which is amplified in certain leukemias, interacts with BLIMP1 leading to a block in BLIMP1 DNA binding activity and a reduction in the ability of BLIMP1 to repress target genes [64][65][66][67][68] . In contrast, the over-expression of the BLIMP1β isoform has been reported in multiple myeloma, DLBCL and in some T cell lymphomas 6,[69][70][71] .…”

MYC as therapeutic target in leukemia and lymphoma

“…68,69 MYC amplification in AML is infrequent, although double minute (dmin) chromosomes and homogeneous staining regions (hsr) including the region 8q24, where MYC maps, have been described in AML. 70,71 MYC overexpression in AML induced resistance to chemotherapeutic drugs. 72 Increased MYC levels were correlated with decreased microRNA-29 family expression in AML.…”