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CELLULAR AND MOLECULAR MECHANISMS OF RADIATION-INDUCED MYELOID LEUKAEMIA IN THE MOUSE

Objective


Male CBA/H mice were irradiated at the age of 3 months with a single X-ray dose of 3 Gy. Acute myeloid leukaemia (AML) was diagnosed on the basis of haematological and pathological examination. The spleen, lymph modes, femoral bone marrow and purified circulating white blood cells were stored in liquid nitrogen. Screenings for oncogenic ras gene mutations were performed on 26 samples. Only one mutation was detected among the 26 AML samples examined, comprising 23 mouse radiation induced AMLs. It thus appears that classical oncogenic ras gene mutations are much less frequent in mouse radiation AMLs than in human AMLs. It should be noted that the majority of the mutations in human AMLs involve the N-ras gene while the only mutation found in this study was located in the K-ras gene.

Myeloid neoplasms in the NFS strain of mice were characterized. Striking properties of myeloid cells obtained from these mice were their rapid adaptation to growth in culture, their differentiated phenotype and the expression in cell cultures of membrane receptors for the neurotransmitter calcitonin gene (CGRP). Such receptors are not commonly found on blood cells but were also found on the human HL60 myelomonocytic cell line. Remarkably HL60 cells express receptors for CGRP only after treatment with differentiation including agents. The work suggests that this murine system is a model for human chronic myeloid leukaemia (CML).

Receptors for neutrotransmitters were also studied in other myeloid lines. These included N122, a 229-Ra-induced myeloid leukaemia and the WEH13 murine myeloid line. The identification of receptors for CGRP on some myeloid cells is promising.

Radiation acute myeloi leukaemia (AML) has been induced in CBA and CBAxC57/Bl F1 mice strains by different qualities of radiation in collaboration with a partner laboratory (ECN Petten NL). Conventional cytogenetic studies followed by fluorescence in situ hybridization (FISH) indicate that deletion of an intestitial segment from chromosome (chr)2 is an early radiation induced event in AML. No evidence for radiation induced genome wide instability was found in AML induced by high or low LET radiations.

Furthur FISH studies followed by molecular analysis of microsatellite DNA losses in AML of F1 mice have identified specific radiosensitive breakpoint regions on chr2, associated these with telomere-like repeat (TLR) DNA sequences and provided evidence on the critical segment on chr2 for gene loss.

Other studies with inbred and F1 mouse strains implies di=ominent inheritence of AML susceptibility but this is no longer believed to map to chr2 ot to involve TLR sequence polymorphism.
Acute myeloid leukemia (AML) may be induced in mice by a single acute dose of XAirradiation. Rearrangements and/or deletions of chromosome 2 might be an initiating event, causally associated with deregulation of the interleukinA1 beta gene and loss of the developmentally important homeobox gene cluster.

However, other factors most probably play also a role in the general process, which might involve the participation of proviral, protooncogene or growth factor genes.

This programme involves experimental approaches aimed towards identifying events that may precede the overt AML. These include the following :
phenotypic characterization of the leukaemic myeloid cells, after generation of monoclonal antibodies;
cytogenetic analysis with particular emphasis on chromosome 2;
characterization of growth factor and growth factor receptor activities and responses;
search for a possible indirect (perhaps virally mediated) mechanism;
molecular studies on the possible involvement of growth factor, receptor and protooncogene sequences.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

BELGIAN NUCLEAR RESEARCH CENTRE
Address
200,Herrmann Debrouxlaan 40-42
1160 Bruxelles
Belgium

Participants (2)

Medical Research Council (MRC)
United Kingdom
Address
20 Park Crescent
W1N 4AL London
NATIONAL RADIOLOGICAL PROTECTION BOARD
United Kingdom
Address

OX11 0RQ Didcot,harwell,chilton