TITLE:
Haploidization of Human Diploid Metaphase Cells: Is This Genome Reductive Mechanism Opperational in Near-Haploid Leukemia?
AUTHORS:
Kirsten H. Walen
KEYWORDS:
Nutritional Replicative Stress; Amino Acid Glutamine; Chromosome/Genomic Aberrations; Small Cells; Proliferative Advantage; Loss of Heterozygosity; Genomic Doubling; Uniparentaldisomy; Endoreplication; Genomic Territories; Nuclear Roundness; Nutritional Insufficiency Autophagy
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.5 No.1,
January
17,
2014
ABSTRACT:
The present study presents cytogenetics/cytology of haploidization in the
origin of a new, fast growing diploid, small cell-type (F-dPCs). The sequence of events was haploid groupings of the
chromosomes in normal, human metaphase cells, followed by genomic doubling to
homozygousdiploidy. These events were responses to DNA
replication stress fromamino acid glutamine deprivation. Importantly, these
homozygous cells outgrew normal fibroblasts in 2 - 3 passages—they had gained proliferative advantage (GPA), presumably from
loss (LOH) of tumor suppressor genes. They were morphologically changed cells
with rounded nuclei that grew in a “streaming” growth pattern and with changed form and size of mitosis, similar to some
hyperplasias. The grouping of the chromosomes in metaphase cells was asymmetric with a narrow range around the median (23) (no micro-nuclei),
suggesting genetic control. The root-origin of haploidization was evidenced by
maternal and paternal genomes occupying separate territories in metaphase
cells, which assumedly permitted independent segregations of bichromatid
chromosomes. In near-haploid ALL-L1 leukemia the loss of virtually, whole
chromosomal complements was judged by SNP array analyses, as a primary event
before genomic doubling to hyperdiploidy with LOH. From the present data such
specific, non-random loss of chromosomes strongly suggested, a haploidization
process capable of genomic doubling, as observed for
the “birth” of the small, F-dPCs. This suggestion was supported by this type of
leukemia being the L1-type, where L1 signifies small cells. The possibility now exists that a tumorigenic process
can be initiated directly from diploid cells through haploid (near-haploid)
distributed chromosomes in normal metaphase cells. This event followed by
monosomic doublings to UPDs would lead to massive LOH and a return to
para-diploidy, a frequent occurrence in many types of tumors. The present
simple, cultural derivations of the extraordinary F-dPCs allow
GPA-identification and experimental manipulations, perhaps relevant in a
vaccine program.