High Incidence of t(7;12)(q36;p13) with Involvement of HLXB9 in Infant AML.

The ETV6/TEL gene (12p13) is rearranged in a spectrum of hematological malignancies resulting in the formation of a functional fusion gene or an ETV6 promoter enforced transcription of over 25 different partner genes. The t(7;12)(q36;p13) is a recurrent translocation with a heterogeneous breakpoint distribution in 7q36. We have shown a fusion transcript between HLXB9 and ETV6 in infant AML with t(7;12), however a fusion transcript is not consistently found. To study the incidence of t(7;12) and the involvement of HLXB9 in infant and childhood acute leukemia we screened 320 infants and pediatric patients younger than 36 months by FISH. We studied the presence of an HXLB9-ETV6 fusion and quantified the expression of various genes in the proximity of the 7q36 breakpoints. Cases studied by FISH included 1) 179 ALL and 54 AML patients younger than 36 months diagnosed in the Netherlands between 1991–1997 or 2003–2004, obtained from the DCOG; (ALL: 14 age 0–12 months, 55 age 12–24 months, 110 age 24–36 months; AML: 16 age 0–12 months, 22 age 12–24 months, 16 age 24–36 months); and 2) 85 infant-ALL from the Interfant-99 study and 2 additional infant-AML. In total, six AML patients were found to carry the t(7;12)(q36;p12) of which 5 were infants and 1 was 18-months old. This indicates that the t(7;12) encompasses 30% of infant AML. In ALL the t(7;12) seems to be uncommon, only one of the 264 patients harbored the t(7;12). The t(7;12) was associated with a poor clinical outcome. A fusion of ETV6 to HLXB9 was found in four AML with t(7;12). The expression of 7q36 genes (HLXB9, NOM1, Lmbr1, RNF32 and SHH) was determined by real-time PCR in several groups: t(7;12)+ cases, t(7;12)- AML, t(7;12)- ALL and healthy individuals. NOM1, Lmbr1, RNF32 and SHH were equally expressed among t(7;12)+ and other groups. However, the HLXB9 expression was highly increased in t(7;12)+ compared to every control group, including those with an HLXB9-ETV6 fusion, suggesting that ectopic expression of HLXB9 is commonly involved in the t(7;12)(q36;p13).