1: Acta Haematol. 2002;107(2):76-94. 

Cytogenetic and molecular genetic evolution of chronic myeloid leukemia.

Johansson B, Fioretos T, Mitelman F.

Department of Clinical Genetics, Lund University Hospital, Sweden.

Chronic myeloid leukemia (CML) is genetically characterized by the presence of
the reciprocal translocation t(9;22)(q34;q11), resulting in a BCR/ABL gene
fusion on the derivative chromosome 22 called the Philadelphia (Ph) chromosome.
In 2-10% of the cases, this chimeric gene is generated by variant
rearrangements, involving 9q34, 22q11, and one or several other genomic regions.
All chromosomes have been described as participating in these variants, but
there is a marked breakpoint clustering to chromosome bands 1p36, 3p21, 5q13,
6p21, 9q22, 11q13, 12p13, 17p13, 17q21, 17q25, 19q13, 21q22, 22q12, and 22q13.
Despite their genetically complex nature, available data indicate that variant
rearrangements do not confer any specific phenotypic or prognostic impact as
compared to CML with a standard Ph chromosome. In most instances, the t(9;22),
or a variant thereof, is the sole chromosomal anomaly during the chronic phase
(CP) of the disease, whereas additional genetic changes are demonstrable in
60-80% of cases in blast crisis (BC). The secondary chromosomal aberrations are
clearly nonrandom, with the most common chromosomal abnormalities being +8 (34%
of cases with additional changes), +Ph (30%), i(17q) (20%), +19 (13%), -Y (8% of
males), +21 (7%), +17 (5%), and monosomy 7 (5%). We suggest that all these
aberrations, occurring in >5% of CML with secondary changes, should be denoted
major route abnormalities. Chromosome segments often involved in structural
rearrangements include 1q, 3q21, 3q26, 7p, 9p, 11q23, 12p13, 13q11-14, 17p11,
17q10, 21q22, and 22q10. No clear-cut differences as regards type and prevalence
of additional aberrations seem to exist between CML with standard t(9;22) and
CML with variants, except for slightly lower frequencies of the most common
changes in the latter group. The temporal order of the secondary changes varies,
but the preferred pathway appears to start with i(17q), followed by +8 and +Ph,
and then +19. Molecular genetic abnormalities preceding, or occurring during, BC
include overexpression of the BCR/ABL transcript, upregulation of the EVI1 gene,
increased telomerase activity, and mutations of the tumor suppressor genes RB1,
TP53, and CDKN2A. The cytogenetic evolution patterns vary significantly in
relation to treatment given during CP. For example, +8 is more common after
busulfan than hydroxyurea therapy, and the secondary changes seen after
interferon-alpha treatment or bone marrow transplantation are often unusual,
seemingly random, and occasionally transient. Apart from the strong phenotypic
impact of addition of acute myeloid leukemia/myelodysplasia-associated
translocations and inversions, such as inv(3)(q21q26), t(3;21)(q26;q22), and
t(15;17)(q22;q12-21), in CML BC, only a few significant differences between
myeloid and lymphoid BC are discerned, with i(17q) and TP53 mutations being more
common in myeloid BC and monosomy 7, hypodiploidy, and CDKN2A deletions being
more frequent in lymphoid BC. The prognostic significance of the secondary
genetic changes is not uniform, although abnormalities involving chromosome 17,
e.g., i(17q), have repeatedly been shown to be ominous. However, the clinical
impact of additional cytogenetic and molecular genetic aberrations is most
likely modified by the treatment modalities used. Copyright 2002 S. Karger AG,
Basel

Publication Types:
    Review
    Review, Tutorial

PMID: 11919388 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


2: Nippon Rinsho. 2001 Dec;59(12):2316-21. 

[Disease-related gene and tumor progression]

[Article in Japanese]

Mitani K.

Department of Hematology, Dokkyo University School of Medicine.

Chronic myelogenous leukemia is a stem cell tumor characterized by the t(9;
22)(q34; 11) translocation generating the BCR/ABL chimeric gene. The BCR/ABL
fusion gene shows several functions, including inhibition of adhesion to stroma
cells and extracellular matrix, activation of mitogenic signalings, inhibition
of apoptosis, and degradation of inhibitory proteins, and thereby causes
transformation of hematopoietic progenitors. Among its functions, the signal
transduction pathways activated by the fusion gene are Ras and MAP kinase
pathways, Jak-Stat pathways, PI3 kinase pathways, and Myc pathways. Molecular
mechanisms in blastic crisis remains largely unknown. However, loss of functions
of tumor suppressor genes such as p53, RB, and p16, activation of oncogene Ras,
overexpression of Evi-1 might be involved in disease progression.

Publication Types:
    Review
    Review, Tutorial

PMID: 11766332 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


3: Rinsho Ketsueki. 2001 Mar;42(3):162-6. 

[Molecular mechanism of leukemogenesis]

[Article in Japanese]

Hirai H.

PMID: 11345775 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


4: Pathol Biol (Paris). 1997 Sep;45(7):556-60. 

[Molecular abnormalities and clonality in myelodysplastic syndromes]

[Article in French]

Fenaux P, Preudhomme C.

Service des Maladies du Sang, CHU de Lille, France.

Few genes have a proven role in the pathogenesis of myelodysplastic syndromes
(MDS). The most common abnormalities involve the RAS genes, most notably the
N-RAS gene, and are present in 10% of cases at diagnosis and in 30% to 40%
during the course of the disease. Mutations of the p53 are found in 5% to 10% of
cases. Mutations of the cFMS genes are less common, abnormalities of the NF1
genes seem to occur only in children, and abnormalities of the RB genes are
exceedingly rare. A few instances of t(5;12) or t(3;21) translocation have been
demonstrated, and their study has provided evidence that the TEL, EVI1, MDS1,
and AML1 genes are involved in some cases of MDS. The presence in MDS of
recurrent chromosome 7, 5q, and 20q deletions suggests that these chromosomal
segments may bear tumor suppressor genes involved in MDS. The gene(s) involved
remain(s) to be identified. Clonality studies have shown that stem cell
involvement usually occurs at the myeloid level and that normal multipotent stem
cells persist in many patients with MDS. This opens up the promising possibility
that transplantation of autologous multipotent stem cells may be an effective
therapeutic approach.

Publication Types:
    Review
    Review, Tutorial

PMID: 9404479 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------