Adele K. Fielding

Antigen receptor gene rearrangements reflect on the heterogeneity of adult Acute Lymphoblastic Leukaemia (ALL) with implications of cell‐origin of ALL subgroups – a UKALLXII study

Cytogenetic and molecular investigations of Acute Lymphoblastic Leukaemia (ALL) have identified the existence of distinct clinical subgroups. Molecular monitoring of clonal Immunoglobulin and T cell receptor (IG/TR) gene rearrangements has become an important tool in stratification of therapy of ALL. In order to determine whether certain features of the patient‐specific rearrangements could hold further prognostic clues or provide information on the cell of origin of ALL, a comprehensive analysis of structural and biological features (V gene usage, coding frame and mutational status and complementarity‐determining region ‐III length) of 473 IG/TR rearrangements identified in 229 adults with ALL was carried out. Distinct variable‐gene usage profiles were identified between ALL subgroups, particularly for patients positive for BCR‐ABL1 compared to MLL‐AFF1 positive leukaemias; suggesting that the former is derived from a more mature B progenitor. Interestingly, occurrence of TRGV1‐TRGV8 was prognostic for better event‐free survival (31% at 4 years with vs. 0% at 4 years without, P = 0·05). The heterogeneity in clinical outcome is suggested by the basic molecular processes of antigen receptor gene rearrangements as shown in this work.

Allogeneic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia (ALL)

Conventional treatment for adult acute lymphoblastic leukemia (ALL) consists of sequentially administered cycles of combination chemotherapy involving an induction, consolidation/intensification, and maintenance phase which is modeled on clinical protocols developed for the treatment of childhood ALL. With this approach, even though a majority of patients (80-92%) achieve complete remission, only one-third of patient or less are long-term survivors. The long-term survival has not changed for over a decade [1-7]. Thus, consolidation of remission is vital in achieving long-term survival in this disease.

Karyotype is an independent prognostic factor in adult acute lymphoblastic leukaemia

Chromosomal translocations lead to oncogene activation in a significant number of haematological malignancies. Those involving the immunoglobulin heavy chain locus, IGH, at chromosome band 14q32 are frequently observed in B-cell malignant proliferation. A small number have been described in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). However, their biological and clinical significance is currently unknown. Detailed fluorescence in situ hybridisation (FISH) and molecular studies were carried out on a series of BCP-ALL patients with chromosomal abnormalities involving 14q32. Novel and recurrent translocations affecting different chromosomes were highlighted. Refined FISH mapping identified putative IGH partner genes at, or flanking, the translocation breakpoints. Four translocations: two previously reported, t(14;19)(q32;q13), t(8;14)(q11;q32), and two novel, t(14;14)(q11;q32)/ inv(14)(q11q32) and t(14;20)(q32;q13), were identified. Molecular analyses showed that four different members of the CAATT enhancer binding protein (CEBP) gene family were involved: CEBPA (19q13, n59), CEBPD (8q11, n58), CEBPE (14q11, n53) and CEBPB (20q13, n52). One patient with a t(14;19)(q32;q13) was observed to involve the fifth family member CEBPG (19q13, n51). Breakpoints were located within the 30 untranslated region (UTR) of CEBPA and either 30 UTR or 50 of CEBPE, whereas breakpoints in 8q11 were B30 kb centromeric of CEBPD. Where material was available, over-expression of target genes was shown by quantitative real-time PCR. Overall, this study has demonstrated for the first time the involvement of five members of the same gene family in a single subtype of haematological disease. It has indicated that transcriptional upregulation of CEBP gene family members, by juxtaposition to IGH, is important in BCP-ALL: a mechanism in complete contrast to that involving CEPBA in acute myeloid leukaemia.