Identification of the TAF15-ZNF384 fusion gene in two new cases of acute lymphoblastic leukemia with a t(12;17)(p13;q12)

We report the clinical, cytogenetic, and molecular data of two patients diagnosed with acute lymphoblastic leukemia characterized by the rare translocation t(12;17)(p13;q12). This translocation has been reported in 25 cases and its putative molecular consequence, the formation of a TAF15-ZNF384 fusion gene, in only six cases. We used fluorescence in situ hybridization followed by long-range polymerase chain reaction to find the translocation breakpoints. A fusion between TAF15 and ZNF384 was identified and confirmed by nucleotide sequencing. Our results confirm that the t(12;17)(p13;q12) leading to a TAF15-ZNF384 fusion gene characterizes a specific subgroup of acute lymphoblastic leukemia and suggest that two different breakpoints in TAF15 may be involved. Whether the two variants of the TAF15-ZNF384 fusion that these correspond to are in any way hematologically or prognostically different, is unknown.     

Philadelphia chromosome positive precursor B-cell acute lymphoblastic leukemia with a translocation t(2;14)(p13;q32)

A female patient with precursor B-cell acute lymphoblastic leukemia (precursor B-ALL) was analyzed cytogenetically. Karyotyping of the leukemic cells showed a Philadelphia chromosome (Ph1), and also showed a translocation between 2p13 and 14q32, which is thought to be specific for children with B-cell chronic lymphocytic leukemia. DNA analysis with both conventional and pulsed-field gel electrophoresis revealed the rearrangement of the c-abl gene, the BCR gene outside the 5.8 kb breakpoint cluster region (bcr or M-BCR), and the comigration of an abnormal Not I pHabl 5' and 3'-bcr fragment, indicating the presence of BCR/c-abl recombination. The JH gene was rearranged, but the JK gene showed a germline configuration, as with previously reported cases with a t(2;14). This case is the first report of a patient with Ph1-positive precursor B-ALL, in whom a specific translocation t(2;14)(p13;q32) is found simultaneously.     

t(12;17)(p13;q21) in early pre-B acute lymphoid leukemia.

Structural rearrangements involving the short arm of chromosome 12 occur in 10% of cases of childhood acute lymphoid leukemia. The translocation t(12;17)(p13;q21), an uncommon 12p abnormality, was identified in five of 2620 cases (0.2%) successfully karyotyped by the Pediatric Oncology Group or St Jude Children's Research Hospital. All five cases were classified as early pre-B; however, CD10 (common acute lymphoblastic leukemia antigen) was expressed at lower levels than other markers of B-cell lineage. Two cases also expressed the myeloid-associated antigen CD33. Leukemic cells were pseudodiploid in four cases, with an extra chromosome 21 in the fifth case. All of these patients achieved complete remission. Two relapsed during subsequent therapy, and three remain in continuous remission for greater than or equal to 20 months.     

t(7;12)(q36;p13) and t(7;12)(q32;p13)--translocations involving ETV6 in children 18 months of age or younger with myeloid disorders.

Our retrospective karyotype review revealed two rare recurrent translocations affecting ETV6 (TEL): t(7;12)(q36;p13) and t(7;12)(q32;p13). Five patients with a t(7;12) were from a group of 125 successfully karyotyped pediatric patients enrolled in consecutive clinical AML trials of the Dutch Childhood Leukemia Study Group over a period of 7 years. During a search of available cytogenetic databases, we found 7q and 12p abnormalities in two additional Dutch patients and in three participants in Pediatric Oncology Group trials. A del(12p) had been initially identified in four of these patients and re-examination of the original karyograms revealed a t(7;12)(q36;p13) in two instances and a probable t(7;12) in the other two. FISH confirmed the presence of a t(7;12)(q36;p13) in the latter. Most (n = 7) also had trisomy 19. The t(7;12)(q36;p13) (n = 9) was more common than the t(7;12)(q32;p13) (n = 1). These subtle translocations were found only in children 18 months of age or younger. A literature search revealed that the t(7;12) with break-points at 7q31-q36 and 12p12-p13 had been reported in six children with myeloid disorders and in two with acute lymphoblastic leukemia; all were 12 months of age or younger. Only two of the 17 for whom survival data were available, were alive after at least 22 months of continuous complete remission. Our findings suggest that ETV6 rearrangements due to a t(7;12) may play an adverse role in myeloid disorders in children 18 months of age or younger. Therefore, children in this age group with myeloid disorders should be screened for both MLL and ETV6 rearrangements.     

Hemophagocytic syndrome complicating T-cell acute lymphoblastic leukemia with a novel t(11;14)(p15;q11) chromosome translocation

A case of hemophagocytic syndrome that developed in a patient with T-cell acute lymphoblastic leukemia (ALL) with a novel chromosome translocation involving 14q11 is reported. A 15-year-old boy with T-cell ALL in relapse showed leukemic cells with an abnormal karyotype of 46,XY,-15,t(11;14)(p15;q11), +der(15)t(15;?)(p11;?). Pancytopenia and extensive hemophagocytosis by macrophages in the bone marrow were observed after reinduction chemotherapy and again at the terminal stage. At autopsy, infiltration of such cells was also found in other organs. The findings suggested occurrence of hemophagocytic syndrome probably associated with cytomegalovirus (CMV) infection. The t(11;14)(p15;q11) may be a novel translocation specific for T-cell ALL, and conceivably, the association of T-cell ALL with the histiocytosis in this patient may not have been coincidental.     

t(4;11)(q21;p15), including one complex translocation t(1;4;11)(p32;q21;p15), in adult T-cell acute lymphoblastic leukemia

We report two adults with T-cell acute lymphoblastic leukemia (ALL). Cytogenetic studies at diagnosis with R banding showed a 46,XX,t(4;11)(q21;p15)/46,XX karyotype in one patient and 46,XY,t(1;4;11)(p32;q21;p15)/46,XY in the other. Fluorescence in situ hybridization with whole chromosome paints (WCP1, WCP4, and WCP11) confirmed the complex rearrangement in the latter patient. Only 10 T-cell ALL patients with the t(4;11)(q21;p15) have been described, all, but one of them, being over 15 years old. Although recurrent in T-cell ALL, its frequency appears to be very low; indeed, it has been identified in only 4 of 193 adults and in 1 of 734 children with T-cell ALL thus far reported in the literature.     

Specific chromosomal aberrations in de novo acute myeloid leukemia: a comparative analysis of results with a report of three novel chromosomal rearrangements t(7;14)(q35;q13), t(8;18)(p11.2;q12), t(13;15) in Indian population

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with regard to morphology, immunophenotype, and genetic rearrangements. Multiple recurrent chromosomal aberrations have been identified by conventional cytogenetic analysis, which is now widely recognized as one of the most important diagnostic and prognostic determinants in AML. Method: Conventional cytogenetic analysis was done on 200 de novo AML subjects. Results: Of these, 176 (88%) were successfully karyotyped and 24 (12%) showed culture failure. Among the176 subjects, 101 (57.4%) were abnormal and 75 (42.6%) showed an apparently normal karyotype. The various aberrations observed were t(8;21)(q22;q22) (5.2%); t(15;17) (q22;q11-21) (9%); t(9;22)(q34;q11)(1.7%); t(14;17)(q32;q11.2)(0.5%); inv(16)(p13;q22)(1.7%); 11q23 rearrangements (4%); monosomy 7 (2.2%) and 22 (1.1%); deletion of 9q (q22q34) (5.1%), 5q (q13q33) (0.5%) and 13q (q13q31) (0.5%); common trisomies like +8 (5.6%), +16 (1.7%), +22 (1.1%), +21 (0.5%), +13 (0.5%), +11 (0.5%), +3 (0.5%); hyperdiploidy (3.4%); hypodiploidy (1.1%); complex karyotype (4%); and other structural abnormalities (4.5%). Apart from these, three novel chromosomal abnormalities viz. t(8;18), t(7;14), t(13;15) were observed in the current study population. Conclusion: This study confirms that the incidence of chromosomal abnormalities varies considerably. Comparatively, the incidence t(15;17), and del9q is higher, while that of −5/del5q, −7/del7q and inv (16) were lower in our population. Similarly, the frequency of other recurrent FAB associated abnormalities viz. 11qabn was comparable to previous reports. Furthermore, ongoing cytogenetic studies are warranted in larger groups of AML cases to identify newly acquired chromosomal aberrations that may aid in cloning novel genes involved in the neoplastic process, ultimately helping in the development of targeted therapeutic drugs.     

Specific chromosomal aberrations in de novo acute myeloid leukemia: A comparative analysis of results with a report of three novel chromosomal rearrangements t(7;14)(q35;q13), t(8;18)(p11.2;q12), t(13;15) in Indian population

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with regard to morphology, immunophenotype, and genetic rearrangements. Multiple recurrent chromosomal aberrations have been identified by conventional cytogenetic analysis, which is now widely recognized as one of the most important diagnostic and prognostic determinants in AML. Method: Conventional cytogenetic analysis was done on 200 de novo AML subjects. Results: Of these, 176 (88%) were successfully karyotyped and 24 (12%) showed culture failure. Among the176 subjects, 101 (57.4%) were abnormal and 75 (42.6%) showed an apparently normal karyotype. The various aberrations observed were t(8;21)(q22;q22) (5.2%); t(15;17) (q22;q11-21) (9%); t(9;22)(q34;q11)(1.7%); t(14;17)(q32;q11.2)(0.5%); inv(16)(p13;q22)(1.7%); 11q23 rearrangements (4%); monosomy 7 (2.2%) and 22 (1.1%); deletion of 9q (q22q34) (5.1%), 5q (q13q33) (0.5%) and 13q (q13q31) (0.5%); common trisomies like +8 (5.6%), +16 (1.7%), +22 (1.1%), +21 (0.5%), +13 (0.5%), +11 (0.5%), +3 (0.5%); hyperdiploidy (3.4%); hypodiploidy (1.1%); complex karyotype (4%); and other structural abnormalities (4.5%). Apart from these, three novel chromosomal abnormalities viz. t(8;18), t(7;14), t(13;15) were observed in the current study population. Conclusion: This study confirms that the incidence of chromosomal abnormalities varies considerably. Comparatively, the incidence t(15;17), and del9q is higher, while that of −5/del5q, −7/del7q and inv (16) were lower in our population. Similarly, the frequency of other recurrent FAB associated abnormalities viz. 11qabn was comparable to previous reports. Furthermore, ongoing cytogenetic studies are warranted in larger groups of AML cases to identify newly acquired chromosomal aberrations that may aid in cloning novel genes involved in the neoplastic process, ultimately helping in the development of targeted therapeutic drugs.     

Abnormalities of chromosome bands 13q12 to 13q14 in childhood acute lymphoblastic leukemia.

PURPOSE: Little is known about nonrandom deletions of chromosome bands 13q12 to 13q14 (13q12-14) in acute lymphoblastic leukemia (ALL). We determined the prognostic significance of cytogenetically identified breakpoints in 13q12-14 in children with newly diagnosed ALL treated on Children's Cancer Group protocols from 1988 to 1995. PATIENTS AND METHODS: Breakpoints in 13q12-14 were identified in 36 (2%) of the 1,946 cases with accepted cytogenetic data. Outcome analysis used standard life-table methods. RESULTS: Seventeen patients (47%) with an abnormal 13q12-14 were classified, according to the National Cancer Institute (NCI), as poor risk, and 15 patients (42%) were standard risk; four (11%) were infants less than 12 months of age. Eight cases had balanced rearrangements of 13q12-14, 27 patients had a partial loss of 13q, and one had both a partial gain and a partial loss. The most frequent additional abnormalities among these patients were an abnormal 12p, a del(6q), a del(9p), a 14q11 breakpoint, and an 11q23 breakpoint. Nineteen patients were pseudodiploid, 10 were hyperdiploid, and seven were hypodiploid. Patients with an abnormal 13q12-14 had significantly worse event-free survival than patients lacking such an abnormality, with estimates at 6 years of 61% (SD = 14%) and 74% (SD = 1%), respectively (P =.04; relative risk = 1.74). Overall survival, however, was similar for the two groups (P =.25). The prognostic effect of an abnormal 13q was attenuated in a multivariate analysis adjusted for NCI risk status and ploidy (P =.72). CONCLUSION: Aberrations of 13q12-14 may contribute to leukemogenesis of childhood ALL and confer increased risk of treatment failure but are associated with other poor-risk features.     

Co-existence of t(6;13)(p21;q14.1) and trisomy 12 in chronic lymphocytic leukemia

We report a case of a 57-year-old man diagnosed with chronic lymphocytic leukemia (CLL) and presence of a rare t(6;13)(p21;q14.1) in association with an extra copy of chromosome 12. Classical cytogenetic analysis using the immunostimulatory combination of DSP30 and IL-2 showed the karyotype 47,XY,t(6;13)(p21;q14.1), +12 in 75% of the metaphase cells. Spectral karyotype analysis (SKY) confirmed the abnormality previously seen by G-banding. Additionally, interphase fluorescence in situ hybridization using an LSI CEP 12 probe performed on peripheral blood cells without any stimulant agent showed trisomy of chromosome 12 in 67% of analyzed cells (134/200). To the best of our knowledge, the association of t(6;13)(p21;q14.1) and +12 in CLL has never been described. The prognostic significance of these new findings in CLL remains to be elucidated. However, the patient has been followed up since 2009 without any therapeutic intervention and has so far remained stable.