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NEOPLASIA
From the MRC Radiation and Genome Stability Unit,
Chilton, Didcot, United Kingdom.
The CBA/H mouse model of radiation-induced acute myeloid leukemia
(AML) was re-examined using molecular approaches. In addition to the
typical promyelocytic AMLs, 34% were reclassified as early pre-B
lympho-myeloid leukemias (L-ML) based on leukemic blood cell
morphology, immunoglobulin heavy-chain gene re-arrangements (IgHR), or expression of both lymphoid
(Vpre-B1 and Rag1) and myeloid (myeloperoxidase
and lysozyme M) genes. Allelic loss on chromosome 4 was frequently
detected in AMLs (53%) and L-MLs (more than 95%), and the
preferential loss of the maternally transmitted allele suggests the
locus may be imprinted. A minimally deleted region (MDR) maps to a
3.4-cM interval, which is frequently deleted in radiation-induced
thymic lymphomas (TLSR5) and contains a recessive, maternally
transmitted genetic locus (Lyr2) that confers
resistance to spontaneous and radiation-induced pre-B and T cell
lymphomas, suggesting they are one and the same. Thus, the
Lyr2/TLSR5 locus is frequently implicated in
myeloid, lymphoid (B and T), and mixed-lineage mouse leukemias and
lymphomas. Epigenetic inactivation of one Lyr2/TLSR5 allele
during normal mouse development suggests that only a single hit is
required for its inactivation during leukemogenesis, and this may be a
significant contributing factor to the efficiency of the leukemogenic
process in the mouse.
(Blood. 2001;98:1549-1554) Genetic alterations that interfere with terminal
differentiation are key events in the evolution of many leukemias. Most
spontaneous human acute leukemias exhibit specific chromosomal
translocations that result in either the enforced expression of an
oncogene or the fusion of genes normally involved in the control of
hemopoietic differentiation.1 Unlike the oncogenic
gain-of-function genetic alterations observed in spontaneous leukemias,
radiation-induced leukemias in mouse and humans exhibit chromosomal
loss,2-11 suggesting that tumor-suppressor gene loss of
function has a role in maturation arrest in radiation-induced
hemopoietic malignancies.
Although radiation-induced leukemias in humans are predominantly
myeloid, both radiation-induced acute myeloid leukemias (AMLs) and
lymphomas have been described in the mouse.2-13 Loss of
function of the Ikaros gene, which is required for the
development of all lymphoid lineages, has been observed in mouse
radiation-induced thymic lymphomas8 The diagnosis of radiation-induced leukemia/lymphoma in the mouse does
not follow the strict criteria used to diagnose human leukemia. For
example, the appearance of metamyelocytes with a thick ring-shaped
nucleus in the leukemic blood is characteristic of mouse
AML,12 though subclassifications have been
proposed.3,13 However, immunophenotype and immunogenotype
analyses of leukemias that arose in X-irradiated Eµ-BCL-2
transgenic mice revealed early B lympho-myeloid leukemia
(L-ML)14 that might have been diagnosed as AML if leukemic
blood cell morphology was the sole criteria used. The
Eµ-BCL-2 L-MLs were attributed to the inhibition of apoptosis by BCL-2 in the normally highly radiosensitive pre-B cells,
yet they arose in a predominantly CBA/H genetic
background,14 and inbred CBA/H mice are susceptible to
radiation-induced AML.12,13
To determine whether the generation of radiation-induced L-ML was
dependent on the anti-apoptotic effects of the BCL-2
transgene in B cell precursor cells and to test the possibility that
some radiation-induced AMLs had been misdiagnosed, we re-examined a panel of mouse leukemias diagnosed as AML by blood cell morphology. Two
thirds were typical AMLs, and one third were early pre-B lympho-myeloid leukemias similar to the radiation-induced Eµ-BCL-2
L-MLs.14 The radioprotective effect of the
BCL-2 transgene is therefore not essential to generate this
type of mixed-lineage leukemia in vivo. Allelic loss on chromosome 4 was frequently detected in both L-MLs (more than 95%) and AMLs
(approximately 50%), as it was in the Eµ-BCL-2
L-MLs.14 A 3.4-cM minimally deleted region (MDR) on
chromosome 4 maps to an interval frequently deleted in radiation-induced thymic lymphomas (thymic lymphoma-suppressor region
5, TLSR5)7 and also contains the recessive maternally transmitted lymphoma resistance 2 (Lyr2) locus.
Lyr2 confers resistance to spontaneous and radiation-induced
pre-B and T cell lymphomas/lymphocytic leukemias,15-17
suggesting that the imprinted locus is involved in most mouse
spontaneous and radiation-induced hemopoietic malignancies, either as a
tumor-suppressor gene or a susceptibility-resistance locus.
Mouse irradiations
Molecular studies
Depending on the degree of splenomegaly, total cellular RNA was also
prepared from approximately half of the leukemic spleen and from
control adult spleen, bone marrow, thymus, and kidney, for Northern
blot analyses.22 RNA (approximately 10-20 µg) was resolved by 1.0% (wt/vol) denaturing gel electrophoresis, transferred to Genescreen membranes, and probed with myeloperoxidase
(MPO),22 lysozyme M (LysM),22
CD19,22 PU1,23 Vpre-B1
(nucleotides 320-866),24 and Rag1 (nucleotides
207-1896)25 cDNA probes. Normal bone marrow and thymus were
used as positive controls for Vpre-B1 and Rag1,
respectively (data not shown). Equivalent RNA loading was confirmed by
ethidium bromide staining or hybridizations with glutathione
peroxidase.26 Probes were labeled with
[
Leukemia presentation AML diagnosis in the mouse relies predominantly on an increased white blood cell count and the appearance of immature myeloid cells in the peripheral blood.12,13,27 Leukemic cells infiltrate the spleen, resulting in splenomegaly, and may be detected in the bone marrow, though bone marrow failure is common. Healthy mouse peripheral blood predominantly contains neutrophils and lymphoid cells (Table 1), and the relative proportion of these cells decreases significantly in myeloid leukemias. As illustrated in Table 1, the distribution of the different immature myeloid cells in the mouse leukemias allows them to be further subclassified (A-D)3,13 in a manner that in some respects is analogous to the French-American-British (FAB) classification of human leukemic bone marrow. In a study involving 1310 X-irradiated mice, 195 myeloid leukemias were diagnosed, and the relative incidence of each leukemia subclass is shown in Table 1.
Leukemia immunogenotype Leukemic spleen DNA samples were immunogenotyped for IgH and TCR- gene rearrangements. Although all
the leukemias had a germline TCR- gene configuration
(TCR-G; data not shown), 34% had
IgH gene rearrangements (IgHR; Figure
1 and data not shown). The relative
proportions of IgHG and
IgHR leukemias in each of the A-D leukemia
subclasses (Table 2) indicate that
although subclasses B and C are most typical of IgHG
leukemias and A and D are most typical of the
IgHR leukemias, there is significant
overlap.
As shown in Figure 1, though mono-allelic (lanes 4, 5, 7, 10) and
bi-allelic (lanes 3 and 8) IgH gene rearrangements were detected, 2 rearranged alleles in addition to the germline
configuration allele (lanes 2, 6, and 11) were also frequently
observed. Although this might be attributed to the presence of
contaminating normal cells in the spleen, the hybridization signal is
variable. In many cases (Figure 1, lanes 2-11 and 13), loss of
heterozygosity (LOH) on chromosome 4 was detectable by polymerase chain
reaction in the same DNA samples, indicating that less than 20%
contaminating normal cells were present in the leukemic spleen (see
below). Furthermore, 3 or more rearranged alleles were also detected in 5 leukemias (Figure 1, lanes 12 and 13, and data not shown), suggesting either the presence of subclonal variants within a clonal leukemia, or
the presence of more than one independently arising leukemia in the
same mouse. Given that the mean latency of the IgHG
and IgHR leukemias is approximately 18 months and that the lifetime incidence of the
IgHR leukemias in irradiated CBA/H (8.7%),
(CBA/H × C57BL/6)F1 (10.1%), F1 × CBA/H (7.9%), F1 × C57BL/6 (7.9%), and F1 × F1 (6.3%) is low, the probability
that 2 or more independent IgHR leukemias arose
in the same mouse at the same (or at a similar) time is negligible.
Multiple IgHR alleles within individual
leukemias (Figure 1, lanes 2, 6, 9, 11-13) most likely represent
subclonal variants of a clonal proB cell leukemia with a leaky
proB(IgHG) Leukemia phenotype To further characterize the IgHG and IgHR leukemias, total cellular RNA was prepared from 71 IgHG and 38 IgHR leukemic spleens and analyzed for the expression of lineage-specific/restricted markers by Northern blot (Figure 2A-B). Because the source of leukemic cells is the leukemic spleen and leukemic cell infiltration into the spleen is variable, only significant differences in the mRNA profile of a leukemic spleen compared to a normal spleen can be attributed to the leukemia cells. Hence, enrichment (+) of an mRNA species in an individual leukemia is defined as more than 2-fold and depletion ( )
as less than 0.5-fold, compared to its level in control spleen (MPO,
CD19, LysM, PU1), or as the presence (+) or absence () when that mRNA
is not detectable in the spleen (Vpre-B1, Rag1). Only large
differences in mRNA levels are considered informative and are larger
than those that might be attributed to gel loading. Leukemias that
contained mRNA levels less than 2 and greater than 0.5 compared to
control spleen are, therefore, not considered informative and are not
scored in Table 3.
As shown in Figure 2A and Table 3 and compared to control spleen, the
typical IgHG leukemia is MPO+ (mean
expression, 54.3 ± 76.8), PU1+ (mean expression,
4.35 ± 3.89), LysM Loss of heterozygosity Allelic loss on chromosome 2 is detected in more than 90% of radiation-induced AMLs in CBA/H mice,3,4,27,31,32 and allelic loss on chromosome 4 is frequently detected in radiation-induced thymic lymphomas and Eµ-BCL-2 L-MLs.5,7,9,11,14,33 Leukemias in this study were screened for LOH on chromosomes 2 and 4. Because most of the leukemias arose in F1 backcross or intercross mice, there is a 50% probability of homozygosity at any given microsatellite marker. Similarly, only those leukemic DNA samples that contain less than 20% contaminating normal cells reveal LOH.4,31,32Thirty AMLs were informative for chromosome 2 LOH
(Chr.2LOH), and the LOH patterns for the 17 AMLs that were
informative (heterozygous) for both proximal and distal breakpoints are
shown in Figure 3A. A 5-cM MDR (47.5-52.5 cM) is defined by LOH patterns E and H (Figure 3A) and is consistent
with the recently defined 0.6-cM MDR (47.5-48.1 cM).32
There was no differential loss of the CBA/H or C57BL/6 allele (18:12,
respectively), consistent with findings of other studies.4,31,32 In contrast, only 2 L-MLs (less than 10%) had detectable Chr.2LOH, indicating that allelic loss on
chromosome 2 is specific for radiation-induced AML.
A similar analysis for chromosome 4 LOH (Chr.4LOH) revealed 15 AML and 25 L-ML informative leukemias. Chr.4LOH patterns for the 34 leukemias heterozygous at both proximal and distal breakpoints are illustrated in Figure 3B. The maternally transmitted CBA/H allele was preferentially lost in both AMLs (9 of 10) and L-MLs (16 of 18) that arose in irradiated CBA/H × (C57BL/6 × CBA/H)F1 backcross mice, and 19 of 28 of these leukemias arose in female mice. However, the D4Mit286 genotype of CBA/H × F1 backcross mice affected with L-ML (homozygous-heterozygous ratio, 19:23) or AML (homozygous-heterozygous ratio, 25:34) revealed no significant excess homozygosity or heterozygosity (P > .5), indicating that there is no genetic linkage between genotype and phenotype at this locus in the CBA/H and C57BL/6 inbred mouse strains. Seventeen AMLs were informative for LOH and were heterozygous on chromosomes 2 and 4. Eight of 17 exhibited Chr.2LOH and an apparently normal chromosome 4; 8 of 17 exhibited Chr.2LOH and Chr.4LOH; and 1 of 17 exhibited Chr.4LOH and an apparently normal chromosome 2. At the level of detection defined by the microsatellite markers used, Chr.2LOH was detected in 94% of AMLs and can be described as a primary genetic lesion, whereas Chr.4LOH was a recurrent (53%) secondary chromosomal abnormality. AML Chr.4LOH patterns define a 5.8-cM (12.1-17.9 cM) MDR (pattern A, Figure 3B), and this is reduced to a 3.4-cM interval (14.5 cM-17.9 cM), when the L-ML LOH patterns (A, B, and G) are included. TLSR5 on chromosome 4 has been mapped to an approximately 20-cM interval centered on D4Mit21 (15.6 cM),7 and, because most of the leukemias in this study exhibit LOH in this region (Figure 3B), allelic loss at TLSR5 is associated with all 3 types of radiation-induced hemopoietic malignancies.
The diagnosis of mouse radiation-induced AMLs has traditionally relied on an increased white blood cell count and the appearance of immature myeloid cells in the blood, bone marrow and spleen,12,13,27 and the subclassification of the AMLs using FAB criteria has been suggested.3,13 Our molecular analyses of 195 leukemias that arose in irradiated mice and that were originally diagnosed as AMLs using leukemic blood cell morphology has revealed 2 distinct malignancies. Sixty-six percent were typical AMLs, and 34% were mixed-lineage early B L-MLs. A screen for LOH on chromosomes 2 and 4 revealed that chromosome 2 allelic loss is specific to the AMLs (more than 90%), but chromosome 4 allelic loss is frequently observed in both AMLs (approximately 50%) and L-MLs (more than 90%). We have mapped a 3.4-cM MDR on chromosome 4 that is common to both radiation-induced AMLs and L-MLs. Allelic loss on chromosome 4 is also frequently observed in radiation-induced thymic lymphomas (a T cell malignancy), and one tumor-suppressor gene locus, TLSR5,7 maps to (or very near) the MDR identified in our study. The lymphoma resistance 2 (Lyr2, 14.5 cM)20 locus that confers a resistance to spontaneous or radiation-induced (pre-B cell) lymphocytic leukemias/lymphomas was fine mapped to this interval by genetic linkage analyses using SL/Kh mice that are highly susceptible to spontaneous pre-B lymphomas and SL/Ni mice that are resistant. Resistance to spontaneous pre-B lymphomas in SL/Ni mice is conferred by a recessive maternally transmitted resistance locus,15-17,34 but there is no linkage between the Lyr2 genotype and phenotype (radiation-induced AML or L-ML) in the irradiated CBA/H × F1 mice in our study. The preferential loss of the maternally transmitted CBA/H allele (25 of 28 leukemias) in the radiation-induced L-MLs and AMLs that arose in our study is consistent with the maternal effects observed at the Lyr2 locus in spontaneous pre-B lymphomas.17 Loss of gene function in the radiation-induced L-MLs and AMLs presumably occurs by the deletion of the active maternally derived allele and the inactivation of the paternal allele by imprinting, and this single hit inactivation of a tumor-suppressor gene may be a contributing factor to the relative efficiency of radiation leukemogenesis in the mouse. The preferential loss of the maternal allele at a different chromosome 4 locus (42.6-55.6 cM) has also been observed in methylene chloride-induced lung carcinoma.35 However, genetic background effects are observed in LOH analyses of radiation-induced thymic lymphomas. The preferential loss of the paternal RF/J allele was observed at the TLSR1 locus (42.6-44.5 cM) in radiation-induced thymic lymphomas that arose in a (C57BL/6 × RF/J)F1 genetic background,5 but not in those that arose in a (C57BL/6 × BALB/c)F1 genetic background.7 The observation that approximately 50% of the mouse radiation-induced AMLs exhibit allelic loss at TLSR5/Lyr2, in addition to the characteristic (more than 95%) allelic loss on chromosome 2, is unexpected given that chromosome 4 aberrations have been infrequently detected (less than 20%) in cytogenetic studies.3,27 As illustrated in Figure 3A, most of the chromosome 2 deletions are large (greater than 20 cM), consistent with the terminal and interstitial deletions involving the loss of approximately 33% to 66% of the approximately 120-cM chromosome observed by cytogenetics.3,27,31,32 In contrast, most (11 of 13) of the AML chromosome 4 deletions are relatively small (less than 10 cM; Figure 3B), representing less than 10% of the whole chromosome, and are presumably too small to detect reliably using conventional cytogenetic methods. There is increasing evidence that gene deletions directly induced by ionizing radiation tend to be considerably larger than those that occur either as an indirect consequence of irradiation or as a consequence of cytoplasmic irradiation.36-38 This raises the possibility that radiation-induced allelic loss on chromosome 2 is the initiating event in mouse myeloid radiation leukemogenesis and that allelic loss at Lyr2/TLSR5 is a recurrent secondary event that arises as an indirect or a delayed effect of the initiating exposure to radiation. The presence of IgH gene rearrangements in approximately
10% of human AMLs39-44 has been attributed to either
lineage infidelity, involving an aberrant differentiation program in
the leukemic cell, or lineage promiscuity of a lympho-myeloid
progenitor cell and the corresponding leukemia.14,43 Pre-B
progenitor cells that can undergo myeloid differentiation under
specific conditions have been detected in vitro,45,46
supporting evidence for the lineage promiscuity model. If the choice of
commitment to a particular lineage is intrinsically flexible and the
differentiation block in the corresponding leukemia is incomplete,
subclonal variants generated by the different maturation options and
external microenvironmental influences available in vivo should be
detected within a clonal leukemia. The detection of more than 2 rearranged IgH alleles within individual leukemias (Figure
1) is consistent with a leaky ProB (IgHG) The involvement of the apparently imprinted Lyr2/TLSR5 locus
in spontaneous and induced myeloid, lymphoid, and mixed-lineage leukemias/lymphomas suggests it may play a key role in the control of
differentiation of multipotential lympho-myeloid progenitor cells. In
many respects, the Pax5 gene is an excellent candidate. B
cell development in Pax5 A second candidate gene that maps to the Lyr2/TLSR5 locus is
the type 1 receptor for transforming growth factor TGF-
We thank T. Ford, J. Neil, M. Cross, N. Kerr, P. Harrison, and T. Tedder for the cDNA probes, and M. Greaves and E. Wright for help in the course of these studies.
Submitted December 4, 2000; accepted May 2, 2001.
Supported by the Medical Research Council and by the Leukaemia Research Fund as part of a Specialist Programme in Radiation Leukaemogenesis. H.C. was supported by an MRC Research Studentship.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Mark Plumb, Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, United Kingdom; e-mail: map12{at}le.ac.uk.
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© 2001 by The American Society of Hematology.
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  M Jawad, G Giotopoulos, C Cole, and M Plumb Target cell frequency is a genetically determined risk factor in radiation leukaemogenesis Br. J. Radiol., September 1, 2007; 80(Special_Issue_1): S56 - S62. [Abstract] [Full Text] [PDF]
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 E. Boulton, C. Cole, A. Knight, H. Cleary, R. Snowden, and M. Plumb Low-penetrance genetic susceptibility and resistance loci implicated in the relative risk for radiation-induced acute myeloid leukemia in mice Blood, March 15, 2003; 101(6): 2349 - 2354. [Abstract] [Full Text] [PDF]
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 E. Boulton, H. Cleary, and M. Plumb Myeloid, B and T lymphoid and mixed lineage thymic lymphomas in the irradiated mouse Carcinogenesis, June 1, 2002; 23(6): 1079 - 1085. [Abstract] [Full Text] [PDF]
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| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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Abstract
Introduction
evidence to support a
role of loss-of-gene function in maturation arrest. However,
inactivation of the p15INK4b cyclin-dependent
kinase inhibitor multitumor-suppressor gene by allelic loss and
promoter methylation has also been detected in radiation-induced thymic
lymphomas (but not myeloid leukemias), indicating that loss-of-gene
function resulting in genetic instability plays a role in
lineage-specific multistage radiation lymphomagenesis.
-32P]-dATP (3000 Ci/mmol; Amersham Pharmacia Biotech,
Amersham, United Kingdom) using the Random Prime Labeling Kit (Life
Technologies, Paisley, United Kingdom). Blots were quantitated using a
Bio-Rad Molecular Imager FX (Bio-Rad Laboratories, Hemel Hempstead,
Bucks, United Kingdom).
pre-B(IgHR) cell differentiation
block. Furthermore, because there was no statistically significant
difference in the incidence of IgHR leukemias in
the inbred CBA/H and the hybrid mice analyzed, the C57BL/6 genetic
background in the backcross and intercross mice is not a confounding factor.
(mean expression, 1.0 ± 1.0), CD19
pre-B
(IgHR) differentiation block.
-radiation-induced mouse primary thymic lymphomas.
Oncogene.
1996;12:669-676
5 locus of the mouse, which appears to be selectively expressed in pre-B lymphocytes.
EMBO J.
1997;6:2267-2272