This is the second report of a large case control study of lymphoma/leukaemia occurring in Yorkshire during 1979-84, and deals with chronic lymphocytic leukaemia presenting either in its haematological (CLL) or more solid lymphomatous (malignant lymphoma-lymphocytic or MLL) forms.
Previously, we identified the chromosomal breakpoint region in leukemias with the common 11q23 translocations and subsequently cloned a gene named MLL that spans the 11q23 breakpoint.
In the first case, the translocation occurred between chromosomes 9 and 11 and the breakpoint at 11q23 localized to the same 9-kilobase region of the ALL-1 gene that is disrupted in most of the de novo leukemias.
A different mechanism of oncogene activation in a leukaemia specific chromosomal abnormality is found for CML, where c-abl sequences are fused into the bcr locus, or in the t(4; 11) of acute childhood leukaemia involving the recently identified ALL-1 gene at chromosome 11q23 resulting in a malfunctioning, structurally altered oncogene.
Southern blot analysis with the partial cDNA clone for the MLL gene at 11q23 which we had isolated previously detected gene rearrangements in all three cell lines and three leukemia samples from the patients with t(11;19) translocation, indicating that these breakpoints were clustered within the 8.5 kb BamHI germline fragment detected by the probe.
The MLL gene involved in 11q23 translocations found in the majority of infantile leukemias and some secondary leukemias makes fusion transcripts with genes such as LTG4 (chromosome 4), LTG9 (chromosome 9), and LTG19 (chromosome 19) as a result of reciprocal translocation.
We describe a case of acute myelomonocytic leukemia (AMML; FAB type M4) with t(10;11)(p13;q23) in which the breakpoint at 11q23 was centromeric to the MLL gene and distinct from the breakpoint seen in promyelocytic leukemias with t(11;17)(q23;q22), thus providing further evidence of heterogeneity of breakpoints in 11q23 in acute leukemia.
These findings support the separation of secondary leukaemia into two classes, and correlate rearrangements of the Htrx-1 gene with a group of secondary leukaemias that follow specific cancer treatment regimens.
To determine whether 11q23/MLL rearrangements were present in the leukemia cells of patients with a normal karyotype, we performed FISH and molecular studies of eight of these patients who had adequate material.
The human tri-thorax gene (HRX) also called ALL-1 (Acute Lymphocytic Leukemia-1) as well as MLL (Myeloid-lymphoid or Mixed-lineage Leukemia) gene, is disrupted in the majority of leukemias with chromosomal abnormalities involving 11q23.
Rare congenital forms of lymphoid or myeloid leukemia, manifested at birth or during the first month of life, carry a dismal prognosis, especially when a MLL/11q23 rearrangement is present; such cases should be carefully distinguished by chromosomal/molecular analysis and cell culture techniques from transient myeloproliferative disorders which require only supportive care but close follow-up for subsequent development of leukemia.
This work provides a clear example of association of a molecular defect with the development of a specific clinical leukemic stage, and supports the indication that ALL-1 gene rearrangement is associated with poor clinical outcome in adult leukemias.
This indicates that both myeloid and lymphoid leukaemias with involvement of the ALL-1 gene can be induced by exogenous agents, especially topoisomerase II inhibitors.
The mixed lineage leukemia/myeloid-lymphoid leukemia (MLL) gene was not rearranged in either case, making these cases distinct from previously described therapy-related leukemias caused by Topo II inhibitors.