The Leukemia-Specific Fusion Gene ETV6/RUNX1 Perturbs Distinct Key Biological Functions Primarily by Gene Repression

-positive leukemic cell lines.-positive ALL samples underline the relevance of these pathways and molecular functions. We also validated six differentially expressed genes representing the categories “stem cell properties”, “B-cell differentiation”, “immune response”, “cell adhesion” and “DNA damage” with RT-qPCR. fusion gene interferes with key regulatory functions that shape the biology of this leukemia subtype. E/R may thus indeed constitute the essential driving force for the propagation and maintenance of the leukemic process irrespective of potential consequences of associated secondary changes. Finally, these findings may also provide a valuable source of potentially attractive therapeutic targets

Prognostic relevance of TLX3 (HOX11L2) expression in childhood T-cell acute lymphoblastic leukaemia treated with Berlin–Frankfurt–Münster (BFM) protocols containing early and late re-intensification elements

TLX3 expression (TLX3+) in childhood T-cell acute lymphoblastic leukaemia (T-ALL) seems to be associated with a poor prognosis when treated with regimens that lack early and/or late re-intensification therapy elements. Because such elements are essential components of the ALL-BFM (Berlin–Frankfurt–Münster) protocols, we evaluated whether TLX3+ T-ALL patients benefit from this type of therapy. Thirty-one/131 childhood T-ALL cases (24%) enrolled into four population-based Austrian ALL-BFM therapy studies were TLX3+. The male to female ratio was 3·5:1 and median age and leucocyte count at diagnosis were 8·7 years and 58·9 × 109/l, respectively. Twenty-four patients (77%) were good responders to prednisone. All were in complete remission after induction therapy. After a median observation time of 4·9 years (range 0·4–16·1 years) 28/31 TLX3+ cases remained in first complete remission after chemotherapy with one after additional stem cell transplantation. Although molecular disease was frequently present after a 4-drug induction therapy, final treatment outcome was excellent indicating that TLX3+ T-ALL cases may benefit from a BFM-type of ALL therapy with early and late re-intensification elements. Moreover, the fact that 2/3 relapses were also NUP214-ABL1+ suggests that these cases might represent the particular risk-prone TLX3+ subgroup that could benefit from a targeted tyrosine kinase inhibitor therapy

Copy Number Changes and Allele Distribution Patterns of Chromosome 21 in B Cell Precursor Acute Lymphoblastic Leukemia

Chromosome 21 is the most affected chromosome in childhood acute lymphoblastic leukemia. Many of its numerical and structural abnormalities define diagnostically and clinically important subgroups. To obtain an overview about their types and their approximate genetic subgroup-specific incidence and distribution, we performed cytogenetic, FISH and array analyses in a total of 578 ALL patients (including 26 with a constitutional trisomy 21). The latter is the preferred method to assess genome-wide large and fine-scale copy number abnormalities (CNA) together with their corresponding allele distribution patterns. We identified a total of 258 cases (49%) with chromosome 21-associated CNA, a number that is perhaps lower-than-expected because ETV6-RUNX1-positive cases (11%) were significantly underrepresented in this array-analyzed cohort. Our most interesting observations relate to hyperdiploid leukemias with tetra- and pentasomies of chromosome 21 that develop in constitutionally trisomic patients. Utilizing comparative short tandem repeat analyses, we were able to prove that switches in the array-derived allele patterns are in fact meiotic recombination sites, which only become evident in patients with inborn trisomies that result from a meiosis 1 error. The detailed analysis of such cases may eventually provide important clues about the respective maldistribution mechanisms and the operative relevance of chromosome 21-specific regions in hyperdiploid leukemias