"CD133-Positive Hematopoietic Stem Cell "Stemness"
Genes Contain Many Genes Mutated or Abnormally
Expressed in Leukemia"
Amos Toren1*, Bella Bielorai1*. Jasmine Jacob-Hirsch1*, Tamar Fisher1*, Doron
Kreiser2, Sharon Zelikson1 David Givol3, Eitan Domany3, Joseph Itskovitz-Eldor 4,
Iris Kventsel1, Esther Rosenthal1, Ninette Amariglio1, Gideon Rechavi1.
From the Department of Pediatric Hemato-Oncology1, and the Department of
Obstetrics and Gynecology2, The Sheba Med Center, Tel-Hashomer, affiliated to the
Sackler School of Medicine, Tel-Aviv University, Israel.
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot
76100, Israel3. Department of Obstetrics and Gynecology, Rambam Medical Center,
Bruce Rappaport Institute of Technology, Technion-Israel Institute of Technology,
Haifa, Israel4
*The first four authors contributed equally to the manuscript
Abstract
Umbilical cord blood (CB) and mobilized peripheral blood (PB) are relatively
new sources of hematopoietic stem cells (HSC) that have been increasingly
used in clinical transplantations. The genetic basis of the underlying
mechanism of HSC self- renewal and differentiation has not been elucidated
yet.
Several groups have recently used microarray technology to study the
common characteristics of stem cells from different tissues (“stemness”) and
the typical features of each source of stem cell ("specificity"). Most groups
focused their study on mice, used relatively small cDNA microarrays, and
used CD34 as the cell surface marker for stem cells isolation.
We studied human stem cells characterized by expression of the more
primitive CD133 antigen, and used the Affymetrix Human Hu133A
oligonucleotide arrays containing 22,215 probe sets to study the expression
profile of these cells.
An unsupervised hierarchical clustering of 14,025 “valid” probe sets showed a
clear distinction between the CD133 + cells representing the stem cell
population, and CD133 – cells that represent various stages of cell
differentiation.
CD133+ cells isolated from CB were compared to CD133- cells identifying
304 genes that were up regulated by at least two folds and the comparison
between PB CD133+ cells and CD133- cells identified 218 genes which were
up regulated by at least two-folds. These genes were considered as source
specific and maybe relevant to the unique properties of CB and PB derived
HSC.
We focused in the 244 genes that were found to be up regulated by
at least two folds in the CD133 positive cells as compared to the CD133
negative cells and were common to both CB and PB. Comparison of
these “stemness” genes, to the lists of “stemness” genes that were identified
by 2 recent studies that analyzed mainly murine HSC identified 33
(Ramalho et al.) and 65 (Ivanova et al.) common genes.
Twenty-four genes were common to another study that analyzed
human HSC (Georgantas et al.).
Among these common “stemness” genes we identified 4 groups of genes that have an
important role in hematopoiesis: Growth factor receptors (Receptor thyrosine kinases
(RTK) and c-mpl), a group of transcription factors which includes several homeobox
genes and TGF-β targeted genes, genes that have an important role in the process of
development and genes involved in cell growth.
Among these 4 groups we identified 16 “stemness” genes (MPL, FLT3,
HOXA9, MEIS 1, MLLT3, KIT, TIE, GATA-2, HOXA5, HOXA10, HLF,
MYCN, EVI1, MYB, FHL1, and HMGA2) that are known to be mutated or
abnormally regulated in acute leukemias.
It can be suggested that perturbation of expression of key hematopoietic
stemness machinery genes may lead to abnormal proliferation and leukemia.