Download Posttranscriptional regulation of posttranscriptional regulators

From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
With this important step forward in understanding follicular lymphoma outcomes, Solal-Céligny and colleagues have brought us closer to a
time when we can both provide a realistic picture
of what the disease has in store for a patient and
individualize the therapeutic approach for this
complex disease. ■
REFERENCES
1. Horning SJ. Natural history of and therapy for the indolent non-Hodgkin’s lymphomas. Semin Oncol. 1993;
20(suppl 5):75-88.
2. Fisher RI. Current therapeutic paradigm for the treatment of
non-Hodgkin’s lymphoma. Semin Oncol. 2000;27(suppl 12):2-8.
3. Peterson BA, Petroni GR, Frizzera G, et al. Prolonged
single-agent versus combination chemotherapy in indolent
follicular lymphomas: a study of the cancer and leukemia
group B. J Clin Oncol. 2003;21:5-15.
4. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project: a predictive model for aggressive nonHodgkin’s lymphoma. N Engl J Med. 1993;329:987-994.
5. Decaudin D, Lepage E, Brousse N, et al. Low-grade
stage III-IV follicular lymphoma: multivariate analysis of
prognostic factors in 484 patients–a study of the groupe
d’Etude des lymphomes de l’Adulte. J Clin Oncol. 1999;
17:2499-2505.
● ● ● HEMATOPOIESIS
Comment on Harris et al, page 1314
Posttranscriptional regulation of
posttranscriptional
regulators
---------------------------------------------------------------------------------------------------------------Steve Collins
FRED HUTCHINSON CANCER RESEARCH CENTER
Posttranscriptional down-regulation of the expression of proteins involved in regulating mRNA processing, nuclear export, and translation occurs during retinoic
acid–induced terminal granulocytic differentiation of cultured leukemia cells.
studying the molecular events involved in the
differentiation of leukemia cells and also likely
provide insight into the molecular regulation
of normal granulopoiesis. In a number of previous microarray studies, extensive changes
in mRNA expression
that occur during
ATRA-induced differentiation of cultured
promyelocytes to
granulocytes have been
well documented. In
those studies that have
combined expression
microarrays with proteomics to study
ATRA-induced granulocytic differentiation,
generally good, although not absolutely
strict, correlation has
been observed between
changes in mRNA ex___.
pression and changes
in protein expression.1
Now, in the present
issue of Blood, Harris
and colleagues have
Matching image analysis for 2-DE. See the complete figure in the article beginsignificantly advanced
ning on page 1314.
yeloid leukemia cell lines induced to
differentiate to granulocytes with
agents such as all-trans-retinoic acid (ATRA)
offer convenient in vitro model systems for
M
1234
such studies using state-of-the-art quantitative
proteomics (the technical details of which are
nicely outlined) to document changes in protein
expression that occur during the ATRAinduced differentiation of the NB4 promyelocytic leukemia cell line. They describe at least 59
proteins that are differentially expressed following
ATRA treatment of these cells, with the majority
of these proteins exhibiting reduced expression.
Many of these down-regulated proteins are involved in posttranscriptional regulation of
mRNA activity and include a number of ribonucleoproteins involved in mRNA processing
and nuclear export as well as other proteins that
regulate mRNA translation. Surprisingly, the
authors observe that for most proteins, the
ATRA-induced down-regulation of these posttranscriptional regulators occurs in the absence
of any documented change in the levels of the
corresponding mRNAs, which essentially remain unchanged in the uninduced versus
ATRA-induced cells. Thus, the down-regulation
of these posttranscriptional mRNA regulators
appears to be in turn regulated by posttranscriptional mechanisms that likely involve either inhibition of mRNA translation or enhanced degradation of the translated protein product.
There are several important take-home
messages from this study. First, the observed
frequent lack of correlation between changes
in protein versus mRNA expression as granulocytic differentiation proceeds provides further evidence that relying solely on RNA expression microarrays without accompanying
proteomic studies can cause one to miss significant changes in the expression levels of
important molecular regulators. Second, the
down-regulation of posttranscriptional
mRNA regulators observed during the terminal differentiation of leukemia cells provides
additional support linking enhanced activity of
such mRNA regulators with the malignant
phenotype. Previous observations have described enhanced expression of particular ribonucleoproteins involved in RNA processing
and nuclear export in BCR/ABL–transformed
hematopoietic cells.2 Moreover, malignancy in
general has been linked with hyperactive
mRNA translation. For example, in certain
model systems, enhanced expression of an
mRNA cap-binding protein eukaryotic initiation factor (eIF-4E) is oncogenic,3 and overexpression of this translational regulator is commonly observed in different human cancers.4
Indeed, the targeted inhibition of mRNA
translational pathways might offer therapeutic
1 SEPTEMBER 2004 I VOLUME 104, NUMBER 5
blood
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
benefit in certain malignancies, and there is
now renewed interest in antitumor agents such
as rapamycin or related compounds that target
(inhibit) specific proteins involved in translational regulation. ■
REFERENCES
1. Lian Z, Kluger Y, Greenbaum DS, et al. Genomic and
proteomic analysis of the myeloid differentiation program:
global analysis of gene expression during induced differentiation in the MPRO cell line. Blood. 2002;100:3209-3220.
2. Perrotti D, Calabretta B. Translational regulation by the
p210 BCR/ABL oncoprotein. Oncogene. 2004;23:32223229.
3. Lazaris-Karatzas A, Sonenberg N. The mRNA 5⬘ capbinding protein, eIF-4E, cooperates with v-myc or E1A in
the transformation of primary rodent fibroblasts. Mol Cell
Biol. 1992;12:1234-1238.
4. De Benedetti A, Graff JR. eIF-4E expression and its role
in malignancies and metastases. Oncogene. 2004;23:31893199.
● ● ● NEOPLASIA
Comment on Harata et al, page 1442, and Zaza et al, page 1435
Targeting
ALL leukemia
---------------------------------------------------------------------------------------------------------------Jerald P. Radich
FRED HUTCHINSON CANCER RESEARCH CENTER
The promise of modern molecular treatments for cancer is that the power of biotechnology will uncover new targets for therapy, killing more cancer while minimizing damage to normal tissues. Two articles in this issue of Blood suggest that
these therapies live up to their promise.
cute lymphoblastic leukemia (ALL) is a
heterogeneous disease consisting of a
wide variety of genetic lesions, including
translocations, hyperdiploidy, and even normal-appearing genotypes.1,2 Successful treatment is the norm for pediatric patients, but
results in adults are far less satisfying. A major
research pursuit is to understand how the different genetic lesions encountered in ALL
map to differences in clinical outcome and
provide insight into new therapeutic options.
In this issue of Blood, 2 studies use novel molecular techniques to uncover new potentially
therapeutic options for subsets of this disease.
Philadelphia chromosome–positive (Ph⫹)
ALL occurs in 5% to 10% of pediatric cases
and in approximately 25% of adult cases. In all
populations, the outcomes following chemotherapy are especially dismal. Recently, the
tyrosine kinase inhibitor imatinib has been
shown to be effective in ALL, but responses
are short-lived, usually lasting only about a
month.3 Resistance in these cases often occurs
from a mutation in the adenosine triphosphate
(ATP)– binding domain of bcr-abl (the chimeric protein coded by the Ph chromosome),
which effectively blocks the action of imatinib.4 There are some suggestions that increasing the imatinib dose may overcome resistance, at least temporarily,5 but increasing
the dose too much invariably leads to toxicity,
since imatinib also blocks the tyrosine kinase
A
blood 1 S E P T E M B E R 2 0 0 4 I V O L U M E 1 0 4 , N U M B E R 5
quantities of free imatinib, as demonstrated
by in vitro culture and annexin V apoptotic
assays. In addition, primary ALL cells from
4 patients were treated in vitro with the antiCD19 liposomal imatinib as well as free imatinib, and these experiments again demonstrated the superiority of the antibodyliposome imatinib. It is instructive that 2 of
these ALL samples had Abl point mutations
yet still were susceptible to the liposomaldelivered imatinib, suggesting that high
concentrations of intracellular imatinib can
indeed overcome the resistance conferred by
the point mutation. Lastly, the liposomal imatinib seemed to have little effect on normal
CD34⫹ as measured in colony-forming assays.
Much may be learned from the “good
risk” leukemia as well as the bad. The TELAML1 fusion gene occurs in approximately
25% of pediatric ALL cases and seems to
identify a cohort with a favorable outlook.6
Why? It is known that de novo purine synthesis (DNPS) is higher in ALL compared
with that of normal bone marrow cells and
peripheral blood lymphocytes; among ALL
cases, T-cell lineage ALL has greater DNPS
than B-lineage ALL.7 Many drugs used in
ALL (such as methotrexate and mercaptopurine) target DNPS and purine metabolism. Zaza and colleagues report on purine
synthesis and metabolism in 113 pediatric
ALL cases, focusing on the differences
across different subtypes of ALL. Their
findings are quite instructive. Among the
function of other nontarget enzymes necessary
for normal organ function. How, then, can one
increase the imatinib effectively delivered to
the ALL cell without harmful effects on normal tissue?
In this issue of Blood, Harata and colleagues report a clever and novel approach
to target imatinib delivery using liposomes
coupled to antibodies to the CD19 antigen.
CD19 is a lymphoid-restricted surface protein, which is found on virtually all Ph⫹
ALL cells as well as
normal B cells. It is
not found on myeloid
or CD34⫹ stem cells.
The authors conjugated mouse monoclonal anti-CD19 antibodies to CD19 with
small (100 nM) liposomes that were
manufactured to encapsulate imatinib.
Using ALL cell lines,
they demonstrated
that these CD19-targeted liposomes
bound and entered
CD19⫹ cells but not
CD19⫺ cells. The
liposomal imatinib
induced greater cell
Internalization analysis of Cal-CD19-liposomes by confocal laser-scanning mideath than equal
croscopy. See the complete figure in the article beginning on page 1442.
1235
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
2004 104: 1234-1235
doi:10.1182/blood-2004-06-2243
Posttranscriptional regulation of posttranscriptional regulators
Steve Collins
Updated information and services can be found at:
http://www.bloodjournal.org/content/104/5/1234.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society
of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.