Balanced Rearrangements of Chromosome 6 in Acute Leukaemia: Clustered Breakpoints in 6q22-q23 and Possible Involvement of c-MYB/AHI1 in a New Recurrent Translocation, t(6;7)(q23;q31).

While deletions of the long arm of chromosome 6 (6q) are common in patients with ALL, translocations are rare, most are considered sporadic and none have been cloned. Among myeloid malignancies, the recurrent translocations: t(6;11)(q27;q23), t(6;11)(q21;q23) and t(6;8)(q27;p11) give rise to known fusion oncogenes. Other uncharacterised balanced or unbalanced 6q abnormalities have occasionally been reported. Using fluorescence in-situ hybridisation (FISH) with HGMP mapped PAC and BAC clones, we investigated chromosomal rearrangements of 6q in acute leukemia. Previously we reported 24 cases with deletions of 6q (Sinclair et al 2004, Can Res 64; 4089), here we describe the analysis of 11 patients with novel balanced rearrangements.

Six of seven breakpoints in ALL and two in a single case of AML were localised to a 10.5 Mb ‘hotspot’ within 6q22–q23. Of these, five were analysed down to the level of a single clone. In two cases of childhood T ALL, both carrying a t(6;7)(q23;q31~36), split FISH signals were produced by adjacent PACs, RP1–32B1 and RP3–388E23, mapping the breakpoints to within a ~150Kb region. A search of published karyotypes identified five similar rearrangements, four also in pediatric T ALL, all present as a sole abnormality or represented in the major clone. Of genes in the region, two (c-MYB and AHI1) are tightly regulated during normal hemopoietic development and over-expression of both has been reported to occur in hemopoietic malignancies. Moreover, clusters of retroviral insertion sites occur within both genes and immediately proximal to c-MYB in murine and feline leukemias and lymphomas. Thus we have defined a new primary recurrent translocation in T ALL that is likely to target either c-MYB and/or AHI1.Three other non recurrent rearrangements of 6q22–q23, mapped in detail, interrupted regions without known genes.. Therefore, these abnormalities were unlikely to have promoted leukemia through classical oncogene activation, but may have influenced expression of one or more common target genes through a long-range position effect. Alternatively these clustered rearrangements may mark the position of a new fragile site on 6q. Additional 6q breakpoints in three cases of AML and one of ALL mapped to 6q15, 6q21, 6q25 and 6q26–q27, and were coincident with the positions of a known oncogene partner AF6q21, the haemopoietic transcription factor BACH2 and two cloned fragile sites FRA6E and FRA6F. Putative partner genes of four translocations were investigated by FISH and the involvement of MLL was demonstrated in one case with t(6;11)(q15;q23).