Hematology 2000
© 2000 The American Society of Hematology
The Molecular Control of Hematopoiesis and Leukemia: From Basic Biology to the Clinic
Leo Sachs, Ph.D., Hon. M.D.
Weizmann Institute of Science, Rehovot, Israel
The establishment of a cell culture system for the clonal development of
hematopoietic cells made it possible to discover proteins that regulate cell
viability, multiplication and differentiation of different hematopoietic cell
lineages, and the molecular basis of normal and abnormal blood cell
development. The first proteins discovered in this way were cytokines, now
called colony stimulating factors (CSFs). They also now include various other
cytokines. There is a network of cytokine interactions, which has positive
regulators such as CSFs and interleukins (ILs) and negative regulators such as
transforming growth factor ß and tumor necrosis factor. This multigene
cytokine network provides flexibility depending on which part of the network
is activated and allows amplification of response to a particular stimulus.
Abnormalities in the developmental program can lead to hematopoietic diseases
including leukemia. Malignancy can be suppressed in certain types of leukemic
cells by inducing differentiation with cytokines that regulate normal
hematopoiesis or with other compounds that use alternative differentiation
pathways. This created the basis or the clinical use of differentiation
therapy. The suppression of malignancy by inducing differentiation can bypass
genetic abnormalities that give rise to malignancy. Different CSFs and ILs
suppress programmed cell death (apoptosis) and induce cell multiplication and
differentiation, and these processes of development are separately regulated.
The same cytokines suppress apoptosis in normal and leukemic cells, including
apoptosis induced by radiation and cytotoxic cancer chemotherapeutic
compounds. An excess of cytokines can increase leukemic cell resistance to
cytotoxic therapy. The tumor suppressor gene wild-type p53 induces apoptosis
that can also be suppressed by cytokines. The oncogene mutant p53 suppresses
apoptosis. A hematopoietic cytokine such as granulocyte-CSF is now used
clinically 1) to correct defects in hematopoiesis, including repair of
radiation- and chemotherapy-associated suppression of normal hematopoiesis in
cancer patients, stimulation of normal granulocyte development in patients
with infantile congenital agranulocytosis, and 2) to increase of hematopoietic
precursors for blood cell transplantation. Treatments that decrease the level
of apoptosis-suppressing cytokines and downregulate expression of
apoptosis-suppressing genes in cancer cells could improve cytotoxic cancer
therapy. The basic studies on hematopoiesis and leukemia have thus provided
new approaches to therapy (reviewed in
1,2,3).
References
-
Sachs L. The adventures of a biologist: prenatal diagnosis,
hematopoiesis, leukemia, carcinogenesis and tumor suppression. Adv
Cancer Res. 1995;66: 1
-40.[Medline]
-
Sachs L. The control of hematopoiesis and leukemia: from basic
biology to the clinic. Proc Natl Acad Sci USA. 1996; 93: 4742
-4749.[Abstract/Free Full Text]
-
Lotem J, Sachs L. Cytokines as suppressors of apoptosis. Apoptosis
. 1999; 187
-196.
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