B lymphoblastic leukemia with ETV6 amplification

We presente a case of acute lymphoblastic leukemia caused by ETV6 amplification. Although the cytogenetic result revealed complex karyotype, multicolor fluorescence in situ hybridization and high-resolution multicolor banding supported amplification of a gene on 12p13. Fluorescence in situ hybridization with ETV6 probe confirmed the amplification. ETV6 generally plays as tumor-suppressor gene in leukemia. Their expression is decreased or missed by deletion or mutation. Otherwise, ETV6 protein overexpression was verified in this case by immunohistochemistry. Any translocation or mutation involving ETV6 was not detected. This experience strongly supports the hypothesis that the amplification of ETV6 is a possible mechanism of leukeogenesis as oncogene.     

The second ETV6 allele is not necessarily deleted in acute leukemias with a ETV6/ABL fusion

The ETV6 (TEL) locus at chromosome band 12p13 is a major site of translocations in acute leukemia, particularly in childhood acute lymphoblastic leukemia (ALL). In cases with translocations involving ETV6, the normal ETV6 allele is often deleted. In addition, loss of heterozygosity of ETV6 is frequently observed in childhood ALL. Thus, it has been suggested that ETV6 may have an anti-oncogenic role to play, in addition to its oncogenic role. We have described an unusual case of ALL in which ETV6 is found fused to the ABL gene; ABL is normally activated by fusion to the BCRgene in the 9:22 translocation. We expanded the primary cells from this ETV6/ABLrearranged case of ALL in SCID animals and analyzed them for expression of both ETV6/ABL and the normal ETV6mRNA. We found that both the rearranged and normal ETV6 mRNAs are expressed in the expanded cell population. Furthermore, sequence analysis of the ETV6 PCR product revealed no point mutations which would influence the amino acid sequence. Thus, deletion of the second ETV6 allele is not necessary for the transformation to leukemia by ETV6/ABL. Genes Chromosomes Cancer 21:256–259, 1998. © 1998 Wiley-Liss, Inc.     

Cytogenetics of long‐term survivors of ETV6‐RUNX1 fusion positive acute lymphoblastic leukemia

This study describes the cytogenetics of 33 children with ETV6‐RUNX1 positive acute lymphoblastic leukemia (ALL) who had been in continuous complete remission for a minimum of 8.8 years [median event‐free survival (EFS) 10.9 years]. The results were compared with a published series of 16 fusion positive patients treated on the same childhood ALL trial, who had relapsed (median EFS, 2.3 years). Interphase fluorescence in situ hybridization (FISH) at diagnosis showed deletion of the second ETV6 signal from all fusion positive cells in 45% of the long‐term survivors but in none of the relapsed patients, whereas patients with mixed populations with retained or lost second signals were more frequent among those who had relapsed (69%) than the long‐term survivors (21%). Interphase populations with two fusion signals in 18% of the long‐term survivors and 31% of relapsed patients were smaller in the long‐term survivors (median, 4% of total cells) than in the relapsed patients (median, 84%). The additional copy of chromosome 21 in 30% of long‐term survivors and in 69% of relapsed patients was a derived chromosome 21 in 20% and 55% of patients, respectively. Metaphase FISH for 26 long‐term survivors and 15 relapsed patients revealed complex karyotypes in both groups. Variant translocations involved different chromosome arms between the long‐term survivors and relapsed patients. It appears that the two groups have some distinguishing cytogenetic features at the time of diagnosis, which may provide pointers to relapse that are worthy of more detailed study. © 2009 Wiley‐Liss, Inc.     

Diffuse large B-cell lymphoma with TEL/ETV6 translocation

Cytogenetic abnormalities of chromosome 12p involving the TEL/ETV6 gene are observed in a variety of hematopoietic neoplasms including acute leukemias, myelodysplastic syndromes, and myeloproliferative disorders. Karyotypic aberrations, including rearrangements, deletions, and amplifications of chromosome 12p, have been documented in B-cell non-Hodgkin lymphoma; however, rearrangements targeting TEL have rarely been reported. Here we describe a diffuse large B-cell lymphoma that had a complex karyotype including t(9;12)(q22;p13), which was confirmed by fluorescence in situ hybridization to represent rearrangement of TEL. Additional cytogenetic abnormalities included t(3;14)(q27;q32) involving the variant, alternative breakpoint region of the BCL6 gene and del(6)(q13q23), resulting in the loss of 1 allele of BLIMP1. This case reiterates the importance of correlating morphologic and phenotypic findings with the results of cytogenetic analysis to avoid errors in diagnosing hematologic neoplasms and highlights the rare association of B-cell non-Hodgkin lymphoma with aberrations of TEL.     

t(7;12)(q36;p13), a new recurrent translocation involving ETV6 in infant leukemia

The ETV6 gene is rearranged as a result of translocations involving a wide variety of chromosomal partners. To date, 12 partner genes for ETV6 have been cloned, and a further 23 chromosomal regions have been described. We previously identified a cryptic t(7;12) with ETV6 involvement in two cases of infant leukemia. The finding of a third case of t(7;12), also in an infant, prompted a more focussed search based on the common features found in these patients and those reported in the literature. The selection criteria were age at diagnosis < 20 months and the presence of +19 and/or +8 in the karyotype; cases with abnormalities of 7q and/or 12p were also considered. FISH studies using whole chromosome paints and probes for the ETV6 gene revealed a t(7;12) in 10 out of 23 cases studied. Seven of these had evidence of ETV6 rearrangement. Of those with ETV6 involvement, six had a 7q36 and one a 7q22 breakpoint. Importantly, in three cases the 7q36 breakpoint was within the same PAC, suggesting the existence of a new nonrandom translocation. However, in at least one patient the 7q36 breakpoint was different. The identification of the 7q partner genes will determine whether it is the disruption of ETV6 alone, or the formation of fusion genes, that is important for leukemogenesis in these patients. As both 7q36 and 7q22 are critical regions of gene loss in del(7q) leukemias, the identification of partner genes from these regions may also be important in understanding the pathogenesis of these diseases.     

Self‐Assembly of ATRP‐Synthesized PCH‐b‐PtBA‐b‐PCH Triblock Copolymers Observed by Time‐Resolved SAXS

The phase behavior of PCH‐b‐PtBA‐b‐PCH triblock copolymers has been studied. Measurements in the wide‐angle region probed the existence of microphase segregation through variation of block mobility and thermal expansion coefficients. SAXS experiments pointed out that most copolymers present ordered nanostructures, mostly hexagonally packed cylinders, the morphology being confirmed by AFM. An unusual disorder‐to‐order transition is observed in one copolymer synthesized from a macroinitiator with intermediate length and the highest outer‐block molecular weight, whereas none of the copolymers shows an order‐to‐disorder transition upon heating over the temperature range analyzed.

     

涎腺类乳腺分泌性癌:对25例标准RT-PCR法未能检出ETV6-NTRK3融合基因病例的进一步分子分析:4例存在ETV6-X融合基因

正ETV6基因异常在肿瘤病理学已有完整描述,据文献报道不同的上皮性肿瘤和血液系统恶性肿瘤可检出多种ETV6融合基因伴侣。在涎腺肿瘤病理中,ETV6-NTRK3易位被认为是乳腺分泌性癌的特异性改变,而在其他类型的涎腺肿瘤中均未见报道。作者分析25例形态学及免疫组化证实的经典乳腺分泌性癌病例,这些病例经FISH检查均显示ETV6重排,但通过标准的RT-PCR方法均未能检测出ETV6-NTRK3融合基因。因此,作者拟通过更为敏感的巢式RTPCR进一步分析ETV6-NTRK3融合基因情况,并探讨其与     

Ectomesenchymoma with t(1;12)(p32;p13) evolving from embryonal rhabdomyosarcoma shows no rearrangement of ETV6

Ectomesenchymoma is a rare mesenchymal malignancy occurring mainly in the pediatric population. The hallmark diagnostic features are a combination of sarcoma, usually rhabdomyosarcoma (RMS) with admixed ganglion cells. The lesion arises either in soft tissues or the cranial cavity, and outcomes vary considerably. Current knowledge about the genetics and biology of ectomesenchymoma is extremely limited with only 4 published karyotypes, showing overlaps only in trisomies 2, 8, and 11. Here, we describe a case with genetic findings that, in conjunction with preexisting observations, offer some additional insights into the genetic aberrations of ectomesenchymoma.     

Abnormalities of the der(12)t(12;21) in ETV6‐RUNX1 acute lymphoblastic leukemia

ETV6‐RUNX1 fusion [t(12;21)(p13;q22)] occurs in 25% of childhood B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) and is associated with a favorable outcome. Additional abnormalities involving der(21)t(12;21) and nonrearranged chromosome 12 are well characterized but aberrations involving the der(12)t(12;21) have rarely been described. Herein, we describe two novel abnormalities affecting the der(12)t(12;21): a deletion (20/247, 8%) and duplication (10/247, 4%). All 30 patients were under 10 years of age, had a median white blood count of 12.4 × 10⁹/L and 19.2 × 10⁹/L, respectively, with a good outcome. Deletions of der(12)t(12;21) on both sides of the breakpoint were confirmed and mapped: centromeric (12p11.21‐12p13.2) and telomeric (21q22.12‐21q22.3). The size of these deletions extended from 0.4–13.4 to 0.8–2.5 Mb, respectively. The centromeric deletion encompassed the following genes: LRP6, BCL2L14, DUSP16, CREBL2, and CDKN1B. We postulate that this deletion occurs at the same time as the translocation because it was present in all ETV6–RUNX1‐positive cells. A second abnormality representing duplication of the reciprocal RUNX1–ETV6 fusion gene was a secondary event, which we hypothesize arose through mitotic recombination errors. This led to the formation of the following chromosome: der(12)(21qter→21q22.12::12 p13.2‐12 p12.3::12p12.3→12qter). Both abnormalities affect the reciprocal RUNX1–ETV6 fusion product which could either eliminate or amplify its expression and thus contribute to leukemogenesis. However, other consequences such as haploinsufficiency of tumor suppressor genes and amplification of oncogenes could also be driving forces behind these aberrations. In conclusion, this study has defined novel abnormalities in ETV6–RUNX1 BCP‐ALL, which implicate new genes involved in leukemogenesis. © 2012 Wiley Periodicals, Inc.     

A child with ALL and ETV6/AML1 fusion on a chromosome 12 due to an insertion of AML1 and loss of ETV6 from the homolog involved in a t(12;15)(p13;q15)

A 4-year-old boy was found to have acute lymphoblastic leukemia characterized by a t(12;15)(p13;q15). FISH investigation using a TEL(ETV6)/AML1 probe detected a fusion signal in 98% of the interphase cells. Sequential FISH on a G-banded slide showed a fusion signal on an apparently normal chromosome 12 and AML1 signals on chromosomes 21. The ETV6 was deleted from the chromosome 12 involved in the t(12;15). These results are best explained as an insertion of AML1 into TEL on one chromosome arm 12p and loss of ETV6 from the chromosome 12 involved in the t(12;15).