A novel t(11;12)(q23-24;q24) in a case of minimally-differentiated acute myeloid leukemia (AML-M0)

Acute myeloid leukemia with minimal signs of myeloid differentiation (AML-M0) is a recent addition to the FAB group classification. Chromosome data is scarce, but existing reports describe a high incidence of complex karyotypes and myelodysplastic syndrome-like chromosome alterations, while single chromosome translocations have rarely been reported. We describe the case of a 60-year-old woman diagnosed with AML-M0 with a novel translocation t(11;12)(q23-24;q24) as the sole karyotypic marker. Fluorescence in situ hybridization analysis to assess MLL gene splitting did not show rearrangement of this oncogene.     

CBFB and MYH11 in inv(16)(p13q22) of acute myeloid leukemia displaying close spatial proximity in interphase nuclei of human hematopoietic stem cells

To gain a better understanding of the mechanism of chromosomal translocations in cancer, we investigated the spatial proximity between CBFB and MYH11 genes involved in inv(16)(p13q22) found in patients with acute myeloid leukemia. Previous studies have demonstrated a role for spatial genome organization in the formation of tumorigenic abnormalities. The nonrandom localization of chromosomes and, more specifically, of genes appears to play a role in the mechanism of chromosomal translocations. Here, two-color fluorescence in situ hybridization and confocal microscopy were used to measure the interphase distance between CBFB and MYH11 in hematopoietic stem cells (HSCs), where inv(16)(p13q22) is believed to occur, leading to leukemia development. The measured distances in HSCs were compared with mesenchymal stem cells, peripheral blood lymphocytes, and fibroblasts, as spatial genome organization is determined to be cell-type specific. Results indicate that CBFB and MYH11 are significantly closer in HSCs compared with all other cell types examined. Furthermore, the CBFB-MYH11 distance is significantly reduced compared with CBFB and a control locus in HSCs, although separation between CBFB and the control is ～70% of that between CBFB and MYH11 on metaphase chromosomes. HSCs were also treated with fragile site-inducing chemicals because both the genes contain translocation breakpoints within these regions. However, treatment with fragile site-inducing chemicals did not significantly affect the interphase distance. Consistent with previous studies, our results suggest that gene proximity may play a role in the formation of cancer-causing rearrangements, providing insight into the mechanism of chromosomal abnormalities in human tumors.     

Translocation (9;11)(p21;q23) in a case of acute myeloblastic leukemia (AML-M2)

A patient with acute myeloblastic leukemia (AML-M2) and a balanced translocation, t(9;11)(p21;q23), is described. The translocation appears to be the same as that previously reported in some patients with acute monoblastic leukemia (AMoL-M5). This suggests that, although t(9;11)(p21;q23) frequently may be associated with AMoL, the translocation may not be specific for that disorder.     

Human homeobox gene HOXC13 is the partner of NUP98 in adult acute myeloid leukemia with t(11;12)(p15;q13)

The chimeric gene NUP98/HOXC13 was detected in a patient with a de novo acute myeloid leukemia and a t(11;12)(p15;q13). Fluorescence in situ hybridization with PAC1173K1 identified the breakpoint on 11p15, indicating that the NUP98 gene was involved in the translocation. At 12q13, the breakpoint fell within BAC 578A18, selected for the homeobox C (HOXC) cluster genes. RACE-PCR showed that HOXC13 was the partner gene of NUP98. To date, HOXC13 is the eighth homeobox gene that, as the result of a reciprocal translocation, fuses with NUP98 in myeloid malignancies.     

Translocation (10;11)(p13;p15) in an infant acute myeloid leukemia with MLL gene rearrangement.

Molecular rearrangements of the MLL gene at the 11q23 region have been identified in most cases of infant leukemia, regardless of the phenotype. We present a case of acute myeloid leukemia which coexpressed myeloid and lymphoid markers in a 12-month-old girl. Karyotype analysis revealed the presence of a thus far unreported translocation t(10;11)(p13;p15). Although no 11q23 abnormalities were cytogenetically detectable, an MLL gene molecular rearrangement was found.     

A NUP98-positive acute myeloid leukemia with a t(11;12)(p15;q13) without HOXC cluster gene involvement

We report a case of adult acute myeloid leukemia with a new t(11;12)(p15;q13) underlying a NUP98 rearrangement without HOXC cluster gene involvement. We designed a specific double-color double-fusion FISH assay to discriminate between this t(11;12)(p15;q13) and those producing NUP98-HOXC11 or NUP98-HOXC13. Our fluorescence in situ hybridization (FISH) showed that putative candidate partners mapping 600 kilobases centromeric to HOXC were RARG (retinoic acid receptor γ), MFSD5 (major facilitator superfamily domain containing 5), and ESPL1 (extra spindle pole bodies homolog 1). It is noteworthy that so far only ESPL1 has been implicated in human cancers. This FISH assay is useful for diagnostic screening of NUP98-positive leukemias.     

Translocation (X;12)(p11;p13) as a sole abnormality in biphenotypic acute leukemia

A reciprocal t(X;12)(p11;p13) was found as the sole clonal abnormality in biphenotypic leukemia with myeloid and B-lymphoid differentiation. With fluorescence in situ hybridization analysis, the ETV6 gene (previously TEL) was found to be translocated intact to the derivative X chromosome; no MLL and BCR/ABL rearrangements were found. The patient achieved complete remission after induction chemotherapy. To our knowledge, this cytogenetic aberration has not been reported previously as a sole abnormality in hematological malignancies. Its presence may suggest an important role in the pathogenesis of biphenotypic leukemia.     

Translocation t(8;16)(p11;p13) in acute nonlymphoblastic leukemia (M4) possibly secondary to Hodgkin's disease

Simultaneous involvement of bands 8p11 and 16p13 in a primary, even though rare, chromosomal translocation recently described in acute nonlymphocytic leukemia may be of crucial interest in some subtypes of this acute leukemia, particularly in the monocytic form. In the present report we describe this translocation in acute nonlymphoblastic leukemia FAB M4, possibly secondary to Hodgkin's disease, though it is also possible that the leukemia may have developed de novo. The aberration t(8;16)(p11;p13) was present in 100% of direct and cultured bone marrow cell preparations. A very high frequency of cells with nonclonal structural chromosome aberrations was also observed in peripheral blood cultures (more than 53%). Random translocations and deletions constituted most of the observed alterations. These findings are discussed with regard to the relationships between secondary leukemias and intensive polychemotherapeutic treatments of primary neoplasias.     

t(5;12)(q13;p13) in acute myeloid leukemia with preceding granulocytic sarcoma

A 56-year-old woman was brought to the emergency room with gum swelling and pain. Biopsy of the gingiva revealed sheet-like proliferation of myeloperoxidase and CD45-positive large cells, and she was diagnosed with granulocytic sarcoma. Two years later, bone marrow involvement of granulocytic sarcoma was suspected. Her chromosome study repeatedly revealed a 46,XX,t(5;12)(q13;p13) karyotype. Case reports of t(5;12)(q13;p13) are extremely rare in the literature. To our knowledge, this is the first report of t(5;12)(q13;p13) in a patient with acute myelogenous leukemia with preceding granulocytic sarcoma.     

Polysomy 13 with concomitant deletion of 13q13-14 involving the retinoblastoma gene and the D13S25 locus in a case of acute myeloid leukemia

We herein describe a case of acute myeloblastic leukemia (AML), FAB subtype M4, with an unfavorable clinical course and a complex karyotype, including 4-9 copies of chromosome 13. Polysomy 13 was a result of clonal evolution. Fluorescence in situ hybridization (FISH) revealed a cytogenetically unrecognizable deletion within 13q13-14 that included the retinoblastoma gene (RB) and the D13S25 locus in all but one copy of chromosome 13. The only chromosome 13 that did not show a deletion affecting the q13-14 region was translocated to chromosome 7, resulting in a dic(7;13)(q21;p11). In this case, the coexistence of polysomy and a partial deletion within the same chromosome point toward a possible formation of a fusion product with oncogenic potential and its consecutive amplification as a critical alteration in this case.     

Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11).

Most myxoid liposarcomas (MLS) are characterized cytogenetically by a t(12;16)(q13;p11). It is reasonable to assume that this translocation corresponds to the consistent rearrangement of one or two genes in 12q13 and/or 16p11, and that the loci thus affected are important in the normal control of fat cell differentiation and proliferation. We have used Southern blot technique to test whether a gene of the CCAAT/enhancer binding protein (C/EBP) family, CHOP, which maps to 12q13 and is assumed to be involved in adipocyte differentiation, could be the 12q gene in question. Using a cDNA probe that spans the CHOP coding region, we detected one rearranged and one wild type allele in nine of nine MLS with t(12;16). Using PCR generated, site-specific probes corresponding to the non-coding exons 1 and 2 and intron 2 of CHOP, rearrangements in five of seven tumors mapped to the 2.4 and 1.6 kbp PstI fragments that contain the first two exons and introns of the gene and the upstream promoter region. In contrast to the findings in MLS, no tumor without a t(12;16) exhibited aberrant CHOP restriction digest patterns. These tumors included one highly differentiated liposarcoma with abnormal karyotype but no involvement of 12q13, seven lipomas with various cytogenetic aberrations of 12q13-15, two uterine leiomyomas with t(12;14) (q14-15;q23-24), and one hemangiopericytoma and one chondroma, both of which also had 12q13 changes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different clones of t(1;12)/t(12;12) involving the ETV6 gene in a case of acute myeloid leukemia

We report a boy with Down syndrome and leukemia who acquired uniparental isodisomy of chromosome 7q as a secondary chromosomal change during recurrence of the disease. His karyotype before therapy was 46,XY,der(1)t(1;1)(p36;q32),-7,+21c/46,idem,del(9)(p22), whereas at recurrence it was 46,XY,der(1)t(1;1)(p36;q32,-7,der(7)(qter-->p22 through pter::q10-->qter),del(9)(p22),+21c/47,XY,+21c. By using polymerase chain reaction amplification of D7S493 and D7S527 markers, we identified the loss of the maternal chromosome 7 with a consequent paternal isodisomy in the clone with dup7q. This rearrangement could be implicated in the progression of the disease by causing (1) nullisomy for a gene or genes located on 7p22-->pter, (2) functional double doses of exclusively paternal expressed genes, and (3) restoration of the effects produced by haploinsufficiency of biparental expressed genes.     

Abnormal chromosome 16 in clonogenic eosinophils from a case of acute myeloid leukemia (FAB,M2)

A case of acute myeloid leukemia (AML, FAB M2) is described in which the leukemic karyotype showed several numerical and structural cytogenetic abnormalities including an abnormal chromosome 16 with breakpoint at band q22, monosomy for chromosomes 5 and 7, and a single pair of double minute chromosomes. There was no patient history of treatment for a previous malignancy or occupational exposure to mutagens. Bone marrow eosinophilia was seen at presentation for refractory anemia with excess blasts in transformation and when AML was diagnosed. When bone marrow buffy coat cells were cultured in soft agar in the presence of colony stimulating factor, 19% of the colonies and 20% of the clusters were of eosinophils. Cytogenetic examination of pooled eosinophil colonies showed the marker chromosomes that identified the leukemic population.     

Disruption of the ETV6 gene as a consequence of a rare translocation (12;12)(p13;q13) in treatment-induced acute myeloid leukemia after breast cancer

We describe a case of treatment-induced acute myeloid leukemia M2 after breast cancer with a rare reciprocal t(12;12)(p13;q13) as a secondary cytogenetic abnormality in addition to the t(11;19)(q23;p13.1). Fluorescence in situ hybridization analysis revealed that both ETV6 genes (previously TEL) were located on the same der(12)t(12;12) as a result of t(12;12). Interestingly, the translocated ETV6 gene was disrupted, indicating the breakpoint on the large der(12)t(12;12) to be within the ETV6 gene and thus the possible formation of a new fusion gene. CHOP gene at 12q13, was found to be translocated intact to the other homologue chromosome 12, indicating that the breakpoint on the small der(12) is proximal to CHOP. To the best of our knowledge, our patient represents the first report of the rare t(12;12)(p13;q13) described in treatment-induced leukemia and the possible formation of a new fusion gene.