The MLL Gene and Translocations Involving …ar.iiarjournals.org/content/25/3B/1931.full.pdf ·...

Abstract. Reciprocal chromosomal translocations are recurrentfeatures of many hematological malignancies. The cloning of thegenes located at the breakpoints of chromosomal translocationsin leukemia and lymphoma has led to the identification of newgenes involved in carcinogenesis. Molecular studies of thebreakpoint of several translocations involving chromosomal band11q23 led to the cloning of a gene that was named MLL. Basedon 7969 cases of acute myeloblastic leukemia (AML) and 1252cases of acute lymphoblastic leukemia (ALL) taken from theliterature, band 11q23 and/or the MLL gene was involved in5.2% of AML and 22% of ALL. Differences in the frequencyand the distribution of translocations were noted according to thetype of acute leukemia and age of the patients. Seventy-fivedifferent rearrangements involving band 11q23 have so far beenidentified, 39 MLL partner genes having been cloned. The fusionof MLL and its partner gene leads to a gain of function of theMLL gene. The accumulating data suggests that the fusionprotein affects the differentiation of the hematopoietic pluripotentstem cells or the lymphoid or myeloid committed stem cells byderegulating the HOX gene expression patterns.

Reciprocal chromosomal translocations are recurrent

features of many hematological malignancies. The cloning

of the genes located at the breakpoints of chromosomal

translocations in leukemia and lymphoma has led to the

identification of new genes involved in carcinogenesis.

These rearrangements mainly lead to the activation of a

proto-oncogene by relocation near active regulatory

sequences [t(11;14)(q13;q32) translocation in mantle cell

lymphoma for example] or the generation of a new gene,called fusion gene [for example t(15;17)(q22;q21) leading to

the PML-RAR· fusion gene] (1, 2). Most of these

rearrangements are unique in that they are identified in

specific leukemia and lymphoma subtypes and that they

involve two specific genes.

Molecular studies of the breakpoint of several

translocations involving chromosomal band 11q23 led to the

cloning of a gene that was named MLL (Mixed-Lineage

Leukemia or Myeloid-Lymphoid Leukemia) (3-8). This

gene is also known as ALL1, HTRX, HRX or TRX1.

MLL abnormalities can be divided in two categories. The

first category consists of MLL rearrangements, usually as

translocations or insertions, some of them cryptic, leading to

fusion genes with a large number of partners (9, 10). It will be

the focus of this review. In addition, self-fusion of two parts

of the MLL within the breakpoint cluster region (bcr), leading

to internal rearrangements called partial tandem duplication

(PTD), have also been described in several cases (11, 12). A

second category of abnormalities is the amplification of the

11q23 region leading to the presence of multiple copies of the

MLL gene, located either intrachromosomally as homo-

geneously staining region (hsr), or extrachromosomally in

double minutes (dmin) (13). Numerical abnormalities of

chromosome 11, such as trisomies or tetrasomies, also result

in additional copies of the MLL gene.

Despite the large variety of rearrangements involving the

MLL gene, the overall prognosis of acute myeloblastic

leukemia (AML) with this abnormality is unfavorable (14,

1931

Presented at the 7th International Conference of Anticancer

Research held in Corfu, Greece from October 25 - 30, 2004.

Correspondence to: Pr. Marc De Braekeleer, Laboratoire de

Cytogénétique, Faculté de Médecine et des Sciences de la Santé,

Université de Bretagne Occidentale, 22, avenue Camille Desmoulins,

CS 93837, F-29238 Brest cedex 3, France. Tel: + 33 (0)2 98 01 64 76,

Fax: + 33 (0)2 98 01 81 89, e-mail: [email protected]

Key Words: MLL gene, chromosomal band 11q23, acute leukemia.

ANTICANCER RESEARCH 25: 1931-1944 (2005)

Review

The MLL Gene and Translocations Involving Chromosomal Band 11q23 in Acute Leukemia

MARC DE BRAEKELEER1,2, FRÉDÉRIC MOREL1,2, MARIE-JOSÉE LE BRIS2,

ANGÈLE HERRY1 and NATHALIE DOUET-GUILBERT1,2

1Laboratoire d’Histologie, Embryologie et Cytogénétique, Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale, Brest;

2Service de Cytogénétique, Cytologie et Biologie de la Reproduction, CHU Morvan, Brest, France

0250-7005/2005 $2.00+.40

15). Therefore, detection of MLL disruption or

amplification is much needed for treatment decision.

Studying the wide variety of fusion genes involving MLLcould also lead to a better understanding of

leukemogenesis.

Distribution of rearrangements involving band11q23 and/or the MLL gene

Numerous studies have calculated the prevalence of

rearrangements of band 11q23 by banding cytogenetics and,

more recently, of the MLL gene by Southern blotting or

fluorescent in situ hybridization (FISH). Differences have

been noted between banding cytogenetics and the other

techniques. Indeed, Southern blotting and FISH are much

more sensitive and allow the recognition of rearrangements of

the MLL gene that are undetected by banding cytogenetics.

Furthermore, although the large majority of 11q23

translocations involves the MLL gene, a few cases of acute

leukemia not involving MLL have been described (16, 17).

A literature search allowed us to identify 7969 cases of

AML and 1252 cases of acute lymphoblastic leukemia (ALL)

that were studied for rearrangements of band 11q23 and/or

the MLL gene (References in Appendix 1). Overall, 5.2% of

AML and 22% of ALL have a translocation involving 11q23

or MLL. Their distribution by age groups shows 58.7% of

the AML and 67.6% of the ALL to have a rearrangement

among patients less than 1 year old (Figure 1). These

frequencies decline steadily among patients less or more

than 15 years old.


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Figure 1. Distribution of 11q23 translocations by age groups and type ofacute leukemia (based on 7969 cases of AML and 1252 cases of ALLfrom the literature).

Figure 4. Distribution of 11q23 translocations in AML by FAB subtypes(based on 3360 cases from the literature).

Figure 3. Distribution of some specific 11q23 translocations by age groupsand type of acute leukemia (based on 7969 cases of AML and 1252 casesof ALL from the literature).

Figure 2. Distribution of some specific 11q23 translocations by type ofacute leukemia (based on 7969 cases of AML and 1252 cases of ALLfrom the literature).

The t(4;11)(q21;q23) translocation is solely observed in

ALL patients and is present in 43.1% of the cases (Figure

2). The second most frequent translocation is

t(11;19)(q23;p13) in ALL (13%). In AML, t(9;11)(p21;q23)

is the most frequent translocation (18.6%). The

t(10;11)(p12;q23) is rare, but still present in 3.9% of AML

patients. A wider variety of other translocations than these

4 is observed in AML (14.7%) than in ALL (8.0%). The

distribution of translocations by type of acute leukemia and

age groups shows that the t(4;11) is almost exclusively

present in ALL infants (less than 1 year old) (Figure 3). In

AML, the frequency of t(9;11) increases with age, while

translocations other than t(4;11), t(9;11), t(10;11) and

t(11;19) are found in all age groups with similar frequencies.

Moreover, the distribution by FAB (French-American-

British) subtypes is available for 3360 of the 7969 AML

cases taken from the literature. Translocations involving

band 11q23 or the MLL gene are more likely to be found in

the M5 (24.9%) and M4 (8.8%) subtypes. No patient among

the 261 with M3 had a 11q23 rearrangement (Figure 4).

In 1998, the European Union Concerted Action

Workshop on 11q23 collected 550 cases of acute leukemia

and myelodysplastic syndromes with a rearrangement of

11q23 (18) (References in Appendix 2). This workshop

confirmed that the t(4;11) is the most frequent translocation

in ALL (68.1%), whereas the t(9;11) and other

translocations are mainly found in AML (41.2% and 14.8%,

respectively) (Figure 5).

De Braekeleer et al: MLL Gene and Acute Leukemia

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Figure 5. Distribution of some specific 11q23 translocations by type ofacute leukemia (based on 550 cases with an acquired abnormality of11q23 reported by the European Union Concerted Action Workshop on11q23 – Secker-Walker, 1998).

Figure 8. Distribution of some specific 11q23 translocations in FABsubtype AML-M5 (based on 550 cases with an acquired abnormality of11q23 reported by the European Union Concerted Action Workshop on11q23 – Secker-Walker, 1998).

Figure 6. Distribution of some specific 11q23 translocations by age groups(based on 550 cases with an acquired abnormality of 11q23 reported bythe European Union Concerted Action Workshop on 11q23 – Secker-Walker, 1998).

Figure 7. Distribution of some specific 11q23 translocations in AML byFAB subtypes (based on 550 cases with an acquired abnormality of 11q23reported by the European Union Concerted Action Workshop on 11q23 –Secker-Walker, 1998).

The distribution of translocations by age groups also

confirms that the t(4;11) is more frequent in infants (less

than 1 year old) (Figure 6), the t(9;11) being fairly equally

distributed among the different age groups and the other

translocations being more frequent after 1 year old. These

differences are partly explained by the preferential

association of some translocations with specific types of

acute leukemia that occur at different ages.

The distribution of the several translocations shows that the

t(9;11) is well represented in the different AML subtypes


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Figure 9. Example of translocation involving the MLL gene.

Figure 10. Exon structure of the MLL gene and location of the breakpoint cluster region (bcr).

(Figure 7). However, this may be misleading; as an example,

there was only one patient with M7. Again, no patient with M3

was found among the 550 patients with 11q23 translocations.

It should also be noted that the patients with M5a are more

likely to have a t(9;11) than patients with M5b, while other

translocations are more frequent in M5b patients (Figure 8).

More recently, Bloomfield et al. published a paper from

an international workshop on balanced chromosome

aberrations in treatment-related myelodysplastic syndromes

and acute leukemia (19). They collected 511 cases, of which

162 had a rearrangement of band 11q23 (31.7%). The

t(9;11) translocation was the most frequent (47.3%),

followed by t(11;19) (21.6%).

All these studies indicate that band 11q23 and the MLLgene are frequently rearranged in de novo and therapy-

related acute leukemia. Furthermore, although some genes

are the preferential partners in most cases, translocations

involving other partner genes are not uncommon (20, 21).

The MLL gene: structure and function

The MLL gene consists of at least 37 exons spanning over

100kb. Sequence analysis of cDNA showed an open reading

frame of some 12kb, encoding for a protein of 3969 amino

acids localizing to nuclear structures (22). Its protein

structure includes several domains (3, 15, 22-30): i) 3 AT

hooks motifs binding to the minor groove of DNA and

influencing the chromatin structure; ii) 1 transcriptional

repression domain including a cysteine-rich region (CxxC)

of homology with DNA methyltransferase, which is involved

in the epigenetic regulation of transcription by methylation

and 2 zinc-finger domains (PHD – plant homology domain)

involved in protein-protein interaction; iii) a

serine/threonine rich region acting as a trans-activator; iv)

a SET domain, in the C-terminal region, the function of

which could be to recruit chromatin remodelling complexes

to specific chromosomal regions

The MLL gene shares 3 regions of homology with the

Drosophila trithorax gene (TRX); these are the 2 zinc-finger

domains and the SET domain. In fact, the MLL gene is the

human homologue of the TRX gene, a member of a highly

conserved family of genes, which regulates the homeotic

gene complex (HOX) by maintaining the transcriptional

states in the later developmental stages (31). The TRXprotein is part of the TAC1 complex that also includes a

histone acetyltransferase (dCBP) and a SET-binding factor

(SEBF1) (32).

Similarly, the MLL protein is part of a larger complex of

at least 27 proteins, whose components are involved in

epigenetic regulation, notably nucleosome remodelling and


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Figure 11. MLL-partner fusion gene structure.

histone deacetylation and methylation (26, 28, 29). Through

direct physical interactions with DNA, MLL binds to

HOXA9 and HOXC8 promoters and regulates specific HOXtarget genes (28, 29, 33). The MLL gene is expressed at high

levels in differentiated myeloid cells, at low levels in stem

cells and lymphocytes, but not in erythrocytes (34, 35).

HOX genes are a major group of transcription factors,

playing a role in the early stages of development and

hematopoietic differentiation, as well as in the later stages

of hematopoietic differentiation with a specific pattern of

expression in different lineages at various differentiation

stages. They are down-regulated upon induction of terminal

differentiation, as the stem cell differentiates into mature

cells (36-39).

MLL fusion genes: structure, chromosome locationand function

Translocations involving band 11q23 usually lead to a

breakage in the MLL gene (Figure 9). The 5’ part of the

MLL gene is retained on the derivative chromosome 11

where it is fused with the 3’ part of the partner gene.

Therefore, the active fusion gene (5’ MLL-3’partner) is

almost always located in the der(11), except in rare cases of

insertion of the 5’ MLL in another chromosome (40).

The breakpoints within the MLL gene cluster in the 8.5kb

region, called the breakpoint cluster region (bcr) located

between exons 5 and 11 (Figure 10) (24, 27, 41, 42). This

leads to a "hot spot" hypothesis supported by the

identification of a cluster of ALU repetitive elements,

recombinase signal sequences, a number of scaffold

attachment regions (SAR) and topoisomerase II consensus

binding sites (25, 27, 43 - 45). The ALU sequences are

located in the centromeric part of bcr, while the

topoisomerase II binding consensus sites are located in the

telomeric portion of bcr. These topoisomerase II binding

consensus sites include 11 sequences closely related to

topoisomerase II consensus binding sites and a perfect

consensus binding site in exon 9 (44, 46).

Acute leukemia and myelodysplastic syndromes secondary

to previous chemotherapy for a primary tumor or leukemia

have a higher frequency of MLL rearrangements if the


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Figure 12. Distribution of the partners of 11q23 translocations or the MLL gene.


1937

Table I. MLL fusion partners: chromosome location and functions.

Name Chromosome Function Other

location names

AF1p 1p32 ·-helical coils EPS15

Probable EGF receptor tyrosine kinase substrate MLLT5

Putative signal transduction

AF1q 1q21 Growth factor

LAF4 2q11-2q12 Putative transcription activator MLLT2

AF3p21 3p21 SH3-containing protein NCK1PSD

Signal transduction?

GMPS 3q24 Cell division

Guanosine monoP synthetase

LPP 3q27-3q28 Putative signal transduction

AF4 4q21 Transcription activator MLLT2

FEL

FLJ10849 4q21 ?

AF5 5q12 Dimerization protein

AF5q31 5q31 Transcription activator

GRAF 5q31 Negative regulator of RhoA KIAA0621

GTPase activating protein for Rho OPHN1L

AF6q21 6q21 Transcription factor FKHRL1

Forkhead DNA binding FOXO3A

AF6 6q27 Signal transduction MLLT4

·-helical coils

CDK6 7q21 Cyclin-dependent kinase 6

AF9 9p22 Transcription activator MLLT3

LTG9

AF9q34 9q34 Negative regulator of RAS proteins activity DAB2IP

DIP1/2

KIAA1743

FBP17 9q34 Telomere maintenance KIAA0554

AF10 10p12 Transcription activator MLLT10

Leucine zipper

ABI1 10p11.2 Cell growth inhibitor E3B1

Signal transduction SSH3BP1

LCX 10q21 Zinc-binding CXXC domain TET1

Methyltransferase domain KIAA1676

CALM 11q14-11q21 Role in integration of signals from different pathways PICALM

CBL 11q23-11q25 Negative regulatory activity in protein CBL2

tyrosine kinase-mediated signaling pathways

therapeutic regimen contained topoisomerase II inhibitors

(epipodophyllotoxins such as etoposide and teniposide) (19,

47). The mechanism of action of the topoisomerase II

inhibitors (including bioflavonoids present in certain fruits

and vegetables, soybean, cocoa, tea, etc.) is still unclear.

Topoisomerase II is an ubiquitous enzyme that facilitates the


1938

Table I. continued.

Name Chromosome Function Other

location names

ARHGEF12 11q23.3 Rho guanine nucleotide exchange factor LARG

KIAA0382

CIP29 12q13 DNA transcription

GPHN 14q23.3 Gly-receptor associated protein GPHRYN

KIAA1385

AF15q14 15q14 Growth repressor

MPFYVE 15q14 Signal transduction?

CBP 16p13.3 Transcription coactivator CREBBP

Histone acetyltransferase activity RTS

RSTS

GAS7 17p13 Growth-arrest specific protein KIAA0394

AF17 17q21 Transcription factor MLLT6

MSF 17q25 Cell cycle regulation? AF17q25

Signal transduction? MSF1

Cytoskeleton organization KIAA0991

Putative GTP binding domain PNUTL4

SEPT9

LASP1 17q11-17q21.3 ? MLN50

LIM

SH3 protein 1

ENL 19p13.3 Transcription activator LTG19

MLLT1

EEN 19p13.3 ·-helical coils SH3GL1

Signal transduction?

ELL 19p13.1 Transcription elongation factor MEN

Regulation of cell growth and survival

hCDCRel-1 22q11.2 Cytoskeleton organization PNUTL1

Putative GTP binding domain CDCRel

AF22

P300 22q13.2 Transcription coactivator E1A

Histone acetyltransferase activity EP300

Cell differentiation

AFX1 Xq13 Transcription factor MLLT7

Forkhead DNA binding FOXO4

Septin 6 Xq22 Cytoskeleton organization KIAA0128

Cytokinesis Septin 2

unwinding of the DNA helix, allowing DNA replication and

transcription. The inhibitors may inhibit the ligase function

of the topoisomerase II enzyme, leaving DNA free ends that

can repair through non-homologous recombination between

the MLL and the partner genes (15, 44, 48-52).

The localization of the topoisomerase II binding

consensus sites in the telomeric portion of bcr may explain

why breakpoints in secondary leukemia and in infant

leukemia have a biased distribution towards the telomeric

portion of bcr, whereas breakpoints in adult de novoleukemia are randomly distributed within bcr (46). These

findings also raise the hypothesis that a maternal dietary

regime rich in bioflavonoids could be involved in

leukemogenesis in utero (51, 53, 54).

Fusion genes keep the AT hook domains and the

methyltransferase domain (transcriptional repression

domain) of MLL, but lack the activation domain and the

SET domain (Figure 11) (30, 42, 55-63). The fusion proteins

consist of the N-terminal portion of the MLL protein fused

to the C-terminal portion of a partner protein. Due to the

loss of the SET domain, histone methylation of the HOXA9and HOXC8 promoters cannot occur (28, 29). This induces

perturbations of HOX gene expression (64).

Partners of translocations involving band 11q23 or the

MLL gene have been localized on all the chromosomes

(Figure 12). A literature search till October 1st, 2004

enabled the recognition of 75 different rearrangements; 28

involving band 11q23 have not been proven to be associated

with a rearrangement of the MLL gene. In 8 different

translocations, fluorescent in situ hybridization showed split

signals of the MLL probe, signing a rearrangement of the

MLL gene. Thirty-nine MLL partner genes have been

identified (15, 25, 27, 30, 48, 53, 56, 65-69). They are

scattered in the whole karyotype. Different partner genes

are located in the same chromosomal band; for example,

AF9q34 and FBP17 are both located in band 9q34 and

ENL, EEN and ELL in band 19p13.

The function, sometimes still putative, of the partners

thus far identified is shown in Table I (42, 56-63, 66). Most

of the MLL partner proteins are distributed in two classes.

Some are transcription and transcription regulator factors,

while others participate in transduction signaling.

The fusion of MLL and its partner gene leads to a gain of

function of the MLL gene (53, 70-73). Two mechanisms have

been proposed. Fusion with nuclear partners having a

transcriptional activation activity induces an increased

transcriptional activation; these fusions are characterized by

a short latency and occur in infant and therapy-related acute

leukemia (for example: AF4, AF9, AF10, ENL). Fusion with

cytoplasmic partners can induce dimerization of MLL, which

results in an increased transcriptional activation; these

fusions are characterized by a longer latency and occur in

adult acute leukemia (for example: AF1p, AF6, EEN).

The MLL fusion genes usually occur in tumors of specific

hematological lineages, leading to the hypothesis that the

MLL partner plays a critical role in determining the disease

phenotype (for example: MLL-AFX1 in T-ALL, MLL-AF4

in B lineage ALL, MLL-EEN in AML, MLL-ENL in

ALL/AML) (66). This suggests that the fusion protein

affects the differentiation of the hematopoietic pluripotent

stem cells or the lymphoid or myeloid committed stem cells.

However, the HOX gene expression patterns appear to be

similarly deregulated, independently of the nature of the

fusion partner gene (64, 74-76).

Several functional consequences of MLL fusion proteins

are known (15, 34, 42, 68, 77-80). MLL fusion proteins can

interfere with cell survival regulation by immortalizing the

committed stem cells and/or by meddling in the apoptosis

process. They can also modify the function of specific

transcription factors controlling myeloid differentiation and

even stop the process. They can disrupt signaling pathways,

notably by interfering with chromatin remodeling.

The hematopoietic pluripotent stem cell alone has the

capability of self-renewal. It gives rise to a multipotent

progenitor having both lymphoid and myeloid potential,

which, in turn, leads to progenitors of lymphoid cells and of

trilineage myeloid cells that are committed to differentiate

into the various blood cells.

Several hypotheses can be formulated (15, 81-85). The

MLL fusion gene is supposedly generated in the

hematopoietic pluripotent stem cell. It could immortalize an

early progenitor cell having both lymphoid and myeloid

potential. It could also induce commitment to a given pathway

(lymphoid or myeloid) followed by differentiation arrest.

Finally, it could stay silent until the transcription programs

that are normally regulated by the MLL gene become active at

a specific differentiation stage in a specific lineage.

In conclusion, much still needs to be learnt about the

function of the MLL gene and its fusion partner genes. This

endeavor will be a major step in understanding normal

hematopoietic development and leukemogenesis.

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1943

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Appendix 2

References of the European Union Concerted Action Workshop on

11q23 used for the calculation of the prevalence of rearrangements

of band 11q23.

1 Bain BJ, Moorman AV, Johansson B, Mehta AB, Secker-Walker

LM and on behalf of the European 11q23 Workshop participants:

Myelodysplastic syndromes associated with 11q23 translocations.

Leukemia 12: 834-839, 1998.

2 Harbott J, Mancini M, Verellen-Dumoulin C, Moorman AV,

Secker-Walker LM and on behalf of the European 11q23

Workshop participants.: Hematological malignancies with a

deletion of 11q23: cytogenetic and clinical aspects. Leukemia 12:

823-827, 1998.

3 Harrison CJ, Cuneo A, Clark R, Johansson B, Lafage-Pochitaloff

M, Mugneret F, Moorman AV, Secker-Walker LM and on behalf

of the European 11q23 Workshop participants: ten novel 11q23

chromosomal partner sites. Leukemia 12: 811-822, 1998.

4 Johansson B, Moorman AV, Haas OA, Watmore AE, Cheung KL,

Swanton S, Secker-Walker LM and on behalf of the European

11q23 Workshop participants: Hematologic malignancies with

t(4;11)(q21;q23) – a cytogenetic, morphologic, immunophenotypic

and clinical study of 183 cases. Leukemia 12: 779-787, 1998.

5 Johansson B, Moorman AV, Secker-Walker LM and on behalf of

the European 11q23 Workshop participants: Derivative

chromosomes of 11q23-translocations in hematologic malignancies.

Leukemia 12: 828-833, 1998.

6 Lillington DM, Young BD, Berger R, Martineau M, Moorman

AV, Secker-Walker LM and on behalf of the European 11q23

Workshop participants: The t(10;11)(p12;q23) translocation in

acute leukaemia: a cytogenetic and clinical study of 20 patients.

Leukemia 12: 801-804, 1998.

7 Martineau M, Berger R, Lillington DM, Moorman AV, Secker-

Walker LM and on behalf of the EU Concerted Action 11q23

Workshop participants: The t(6;11)(q27;q23) translocation in

acute leukemia: a laboratory and clinical study of 30 cases.

Leukemia 12: 788-791, 1998.

8 Moorman AV, Hagemeijer A, Charrin C, Rieder H, Secker-

Walker LM and on behalf of the EU Concerted Action 11q23

Workshop participants: The translocations, t(11;19)(q23;p13.1)

and t(11;19)(q23;p13.3); a cytogenetic and clinical profile of 53

patients. Leukemia 12: 805-810, 1998.

9 Secker-Walker LM, Moorman AV, Bain BJ, Mehta AB and on

behalf of the EU Concerted Action 11q23 Workshop: Secondary

acute leukemia and myelodysplastic syndrome with 11q23

abnormalities. Leukemia 12: 840-844, 1998.

10 Secker-Walker LM and on behalf of the European 11q23

Workshop participants: General report on the European Union

Concerted Action Workshop on 11q23, London, UK, May 1997.

Leukemia 12: 776-778, 1998.

11 Swansbury GJ, Slater R, Bain BJ, Moorman AV, Secker-Walker

LM and on behalf of the European 11q23 Workshop participants:

Hematological malignancies with t(9;11)(p21-22;q23) – a laboratory

and clinical study of 125 cases. Leukemia 12: 792-800, 1998.

Received December 28, 2004Accepted February 23, 2005


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