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PubMed2001

Identification of new translocations involving ETV6 in hematologic malignancies by fluorescence in situ hybridization and spectral karyotyping.

TEL/ETV6 is the first transcription factor identified that is specifically required for hematopoiesis within the bone marrow. This gene has been found to have multiple fusion partners; 35 different chromosome bands have been involved in ETV6 translocations, of which 13 have been cloned. To identify additional ETV6 partner genes and to characterize the chromosomal abnormalities more fully, we studied bone marrow samples from patients known to have rearrangements of 12p, using fluorescence in situ hybridization (FISH) and spectral karyotyping (SKY). FISH analysis was done with 14 probes located on 12p12.1 to 12p13.3. Nine ETV6 rearrangements were identified using FISH. The aberrations include t(1;12)(p36;p13), t(4;12)(q12;p13) (two patients), t(4;12)(q22;p13), t(6;12)(p21;p13), der(6)t(6;21)(q15;q?)t(12;21)(p13;q22), t(6;12)(q25;p13), inv(12)(p13q24), and t(2;2;5;12;17)(p25;q23;q31;p13;q12). Six new ETV6 partner bands were identified: 1p36, 4q22, 6p21, 6q25, 12q24, and 17q12. Our present data as well previous data from us and from other researchers suggest that ETV6 is involved in 41 translocations. The breakpoints in ETV6 were upstream from the exons coding for the HLH (helix-loop-helix) domain in six cases. Although cytogenetic analysis identified 12p abnormalities in all cases, FISH and SKY detected new and unexpected chromosomal rearrangements in many of them. Thus, complete characterization of the samples was achieved by using all three techniques in combination.

Adolescent↗
PubMed1998

Fluorescence in situ hybridization characterization of new translocations involving TEL (ETV6) in a wide spectrum of hematologic malignancies.

The ETV6 (also known as TEL) gene on chromosome 12p13 is the target of a number of translocations associated with various hematologic malignancies. The contribution of ETV6 to leukemogenesis occurs through different mechanisms that involve either its helix-loop-helix dimerization domain or its E26 transformation-specific (ETS) DNA-binding domain. Using fluorescence in situ hybridization we characterized seven new ETV6 rearrangements in chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and non-Hodgkin's lymphoma. These aberrations, not always discernible at the cytogenetic level, include a t(5;12)(q31;p13), t(6;12;17)(p21;p13;q25), t(7;12)(p15;p13), t(7;12)(p12;p13), t(7;12)(q36;p13), t(12;13)(p13;q12), and a not completely defined t(12;?)(p13;?). Loss or disruption of the second ETV6 allele by a del(12)(p12p13) or by an intragenic ETV6 deletion was detected in two cases. In six cases the 12p13 breakpoint occurred in the 5' end of ETV6, upstream to exons encoding the HLH domain, whereas the remaining case had a breakpoint between the exons coding for the HLH domain and the exons coding for the ETS domain of ETV6. These observations provide further evidence for the multiple contributions of ETV6 in the pathogenesis of a wide range of hematologic malignancies.

Adolescent↗
PubMed1997

ETV6 is the target of chromosome 12p deletions in t(12;21) childhood acute lymphocytic leukemia.

The presence of ETV6 deletions was investigated in 215 children with acute lymphoblastic leukemia (ALL) using the loss of heterozygosity (LOH) approach. We used four intragenic or juxtagenic microsatellite markers to detect allelic deletions. In this series of unselected patients, LOH of ETV6 markers was found in 23% of cases (6% of T-ALL and 26% of B lineage ALL) confirming that chromosome 12p12-13 deletions represent a major genetic alteration in childhood ALL, frequently missed by cytogenetic analysis. The presence of a t(12;21)(p13;q22) was studied by RT-PCR and/or FISH in a total of 134 patients (125 B lineage ALL, nine T-ALL) including 42 cases with LOH. Thirty-four out of 44 patients (77%) for whom a t(12;21) was observed displayed LOH of the ETV6 markers. When associated with a t(12;21), ETV6 is very likely to be the target of deletions as indicated by the detection of intragenic deletions in three patients. Although deletion of ETV6 and t(12;21) were associated in most patients, in eight cases (six B lineage and two T-ALL) LOH was detected at the ETV6 locus without ETV6-AML1 hybrid RNA. FISH studies conducted in five of these eight patients confirmed the absence of translocation involving ETV6. In such patients, the other allele of ETV6 could be disrupted by either a small deletion, a point mutation, or an epigenetic modification and it will be of interest to study the structure and expression of the remaining allele of ETV6 in these cases. Alternatively, a tumor suppressor gene located close to ETV6 and CDKN1B could be the target of deletions.

Adolescent↗
PubMed2000

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).

Child, Preschool↗
PubMed2000

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.

Chromosome Breakage↗
PubMed2006

High incidence of t(7;12)(q36;p13) in infant AML but not in infant ALL, with a dismal outcome and ectopic expression of HLXB9.

The t(7;12)(q36;p13) is a recurrent translocation involving the ETV6/TEL gene (12p13) and a heterogeneous breakpoint at 7q36. A fusion transcript between HLXB9 and ETV6 in AML with t(7;12) is occasionally found. To study the incidence of t(7;12) in infant and childhood acute leukemia, we screened 320 cases <36 months using FISH. Additionally, 28 pediatric cases >36 months with cytogenetic breakpoints at 12p and 7q were investigated. We studied the presence of an HXLB9-ETV6 fusion transcript and quantified the expression of various genes located in the 7q36 breakpoint region. In total, six AML patients carried the t(7;12) of which five were infants and one child of 18 months. Only one out of 99 infant ALL patients harbored the t(7;12). No t(7;12) was found in older children with AML or ALL. AML patients carrying a t(7;12) had a poor outcome with a 3-year EFS of 0%. A fusion of HLXB9 to ETV6 was found in four AML cases with t(7;12). The 7q36 genes NOM1, LMBR1, RNF32, and SHH were equally expressed among t(7;12)-positive AML versus t(7;12)-negative AML, t(7;12)-negative ALL, or normal bone marrow. However, the HLXB9 expression was highly increased in t(7;12)-positive cases, including those with an HLXB9-ETV6 fusion. We conclude that the t(7;12) is almost exclusively present in infant AML and covers 30% of infant AML, while it is extremely rare in infant ALL and older children. The t(7;12) is associated with a poor outcome and an ectopic expression of HLXB9 is commonly involved in this genetic subtype of leukemia.

Acute Disease↗
PubMed2004

TEL/AML1 shows dominant-negative effects over TEL as well as AML1.

The TEL/AML1 chimeric gene is generated by the t(12;21) translocation in pre-B cell acute lymphoblastic leukemia. TEL/AML1 consists of the helix-loop-helix (HLH) dimerization domain from TEL and almost the entire of AML1, but loses the ETS DNA-binding domain from TEL. Dominant-negative effects of TEL/AML1 over wild-type-AML1 are believed to trigger the development of this type of leukemia. However, it could also be possible that TEL/AML1 affects wild-type-TEL's molecular and tumor suppressive functions through the HLH domain. To test this possibility, we first confirmed that TEL/AML1 associates with wild-type-TEL. TEL/AML1 neither bound to the ETS-binding consensus site nor repressed transcription through it. Regardless, this prevented wild-type-TEL-induced transcriptional repression. Moreover, TEL/AML1 concomitantly inhibited wild-type-TEL-induced growth suppression and wild-type-AML1-mediated transforming activity in NIH3T3 cells. All these data indicate that TEL/AML1 exerts dominant-interfering effects on both AML1 and TEL, and that expression of TEL/AML1 could result in inactivation of TEL's tumor suppressive functions in t(12;21)-carrying leukemia.

Animals↗
PubMed1999

Loss of the TEL/ETV6 gene by a second translocation in ALL patients with t(12;21).

Inactivation of the non translocated TEL/ETV6 gene is commonly associated with translocation (12;21) of acute lymphoblastic leukemia (ALL). Translocations involving the short arm of chromosome 12 were analysed in two children with t(12;21) ALL. Fluorescence in situ hybridation studies showed that these associated translocations resulted in loss of TEL/ETV6. While hybridization with a YAC probe covering TEL/ETV6 was positive in one patient, analysis with cosmid probes covering the gene demonstrated that the gene was in fact deleted. It is concluded that deletions involving TEL/ETV6 can remain undetected by FISH using only YAC probes.

Adolescent↗
PubMed1997

Low frequency of TEL/AML1 in adult acute lymphoblastic leukemia.

Translocation (12;21)(p13;q22) is a recently characterized aberration in acute lymphoblastic leukemia, and results in the fusion of the TEL and the AML1 genes. It is the most common translocation in pediatric acute lymphoblastic leukemia (ALL), occurring in about one third of the cases. To determine the frequency of TEL/AML1 in adult ALL, we studied 4 cases of T lineage ALL and 26 cases of B lineage ALL. Only one positive case was identified, giving a very low frequency of 3.3%. In this patient, TEL/AML1 was still detectable in complete hematologic remission. The apparent age predilection of t(12;21) warrants further investigations.

Adolescent↗
PubMed1999

A new translocation, t(2;4;12)(p21;q12;p13), in CD7-positive acute myeloid leukemia: a variant form of t(4;12).

We describe a 41-year-old man with CD7-positive acute myeloid leukemia (AML-M0) with trilineage-myelodysplasia. Chromosome analysis of the bone marrow cells showed 46.XY.t(2;4;12) (p21;q12;p13). Cytological and clinical features of our case were quite similar to those of AML with t(4;12)(q11-12;p13). The karyotypic interpretation was confirmed by fluorescence in situ hybridization (FISH) by using the whole-chromosome painting probes specific for chromosomes 2, 4, and 12. FISH analysis with the use of the YAC 936e2 probe, which covers the TEL gene, did not show the split signal, suggesting that a gene other than TEL was involved in the leukemogenesis of the present case. Our case with AML with t(2;4;12)(p21;q12;p13) appears to be the first case of a variant type of AML with t(4;12) (q11-12;p13).

Acute Disease↗
PubMed2000

Interstitial deletion of the short arm of chromosome 12 during clonal evolution in myelodysplastic syndrome with t(5;12)(q13;p13) involving the ETV6 gene.

We report here a 65-year-old man with a myelodysplastic syndrome (MDS), refractory anemia with excess of blasts. He had received chemotherapy with tegafur for renal carcinoma. Chromosome analysis of bone marrow cells revealed complex karyotypes; del(5)(q13) was observed in all 20 metaphase spreads, and two related aberrations, add(12)(p11) and add(12)(p13), were detected in 13 and 7 cells, respectively. Fluorescence in situ hybridization (FISH) analysis with chromosome-specific DNAs revealed that these alterations originated from a reciprocal translocation (5;12)(q13;p13). Therefore, del(5)(q13), add(12)(p11), and add(12)(p13) were revised as der(5)t(5;12)(q13;p13), der(12)del(12)(p11p13)t(5;12)(q13;p13), and der(12)t(5;12)(q13;p13), respectively. Fluorescence in situ hybridization with a series of cosmid probes spanning the ETV6 gene showed that the 12p13 breakpoint on the der(12)t(5;12)(q13;p13) was located in intron 1, but the exon 1 signal was deleted. Our results suggest that a fusion gene was generated between the 5'-end of an unidentified partner at 5q13 and the 3'-end of ETV6 by t(5;12)(q13;p13), and that the interstitial deletion (12)(p11p13) occurred following t(5;12) during clonal evolution. del(12)(p11p13), including the rearranged ETV6 gene, may be implicated in the progression of MDS.

Aged↗
PubMed1997

TEL gene rearrangements in myeloid malignancy.

The TEL gene is a recently described, "promiscuous" gene with a role in both myeloid and lymphoid malignancy. It is unusual since there may be more than one mechanism by which its rearrangement through chromosomal translocation is leukemogenic. This article discusses the four potential mechanisms of TEL-mediated transformation. It is conceivable that the TEL gene is the common target for various translocations precisely because of this pleiotropy of pathogenic mechanisms by which TEL gene rearrangements can lead to cell transformation.

Amino Acid Sequence↗
PubMed1997

TEL/AML1 fusion gene resulting from a cryptic t(12;21) is uncommon in adult patients with B-cell lineage ALL and CML lymphoblastic transformation.

TEL is a new member of the ETS-like family on chromosome 12 and forms fusion genes with several partners in leukemia. Among these fusion genes, the TEL/AML1 translocation resulting from t(12;21) is found in approximately one quarter of the childhood B-cell lineage acute lymphoblastic leukemia (ALL) cases and its prognosis is excellent. We examined 42 adult patients with B-cell lineage ALL and 13 adult patients with lymphoblastic transformation of chronic myeloid leukemia (CML) to detect TEL/AML1 fusion genes using the reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blotting, but no translocation was detected. These findings indicate that absence of the TEL/AML1 fusion transcript partly correlates with the poorer outcome of adult B-cell lineage ALL as compared with childhood ALL and the TEL/AML1 fusion transcript is specific for pediatric B-cell lineage ALL.

Adolescent↗
PubMed2003

Regulation of cytokine receptor signaling by SOCS1.

The suppressor of cytokine signaling (SOCS) family of proteins is a novel class of negative feedback regulators of cytokine receptor signaling. SOCS1 is rapidly induced following stimulation by several type I and type II cytokines, and it attenuates their signaling by its ability to bind and inhibit all four of the Janus family of intracellular tyrosine kinases (JAKs). Studies from our own and other laboratories have documented another important function of SOCS1 in facilitating ubiquitination of protein substrates and their subsequent proteasomal degradation. SOCS1 also functions as a potential tumor suppressor by inhibiting several hematopoietic oncogenes. In addition to these negative regulatory functions, we have recently shown a positive regulatory role for SOCS1 in increasing the stability of major histocompatibility complex (MHC) class II proteins by preventing their degradation. These findings illustrate multiple roles for SOCS1 in cytokine receptor signaling, and provide groundwork for detailed analysis of the role of SOCS1 in pre-T cell receptor (TCR) and TCR signaling, and regulation of T helper (Th)1 and Th2 differentiation.

Animals↗