Val Bejarano

Article Summary
Bio 1615

KRAS initiated Leukemia Summary

Cancer is known for its ability to self renew in an out of control fashion producing
tumors and ultimately, death. Oncogenes are the genes that produce the signals to self renew,
however, not much about how these oncogenes is fully understood. This scientific research paper
attempts to address and locate how certain mutations and Kirsten Rat Sarcoma Viral Oncogene,
otherwise known as KRAS can initiate Leukemia in Hematopoietic Stem Cells.
RAS proteins like KRAS and NRAS are essentially relay switches. These proteins trigger
the cells from outside with on/off growth signals. Approximately 1/3 of human malignancies
display an RAS gene mutation which affects these growth signals. As mentioned above, cancer
affects the protein signaling mechanism, causing the phenotype most identified with cancer,
malignant tumors.
Mutated RAS proteins in mice led to a disease very similar to leukemia developed in
humans. This leukemia is known as a myeloproliferative disorder. These mutations in mice did
not stay static, they evolved. Mice that had these cancer stem cells developed acute lymphoid
leukemia after daughter cells developed subsequent mutations. This observation shows that
subsequent daughter cells from initially infected stem cells or bone marrow cells develop change
as the cancer grows and progresses.
RAS gene protein cancers are not only isolated to leukemia, but are actually found in a
wide range of cancers. Pancreatic, Rectal, Lung, Endometrial and Cervical cancers are all

Val Bejarano
Article Summary
Bio 1615
affected by RAS mutations. Of these RAS gene mutations, KRAS is the responsible for over
90% of actual mutations.
Although this study covered the effects of KRAS mutations in the cell cycle and
identification, the most intriguing part of the study is how KRAS, transplanted into Thymocytes
who acquire a Notch1 mutation, led to T-cell acute lymphoblastic leukemia or T-ALL. All mice
specimens transplanted with KRAS affected cells died within 8 to 14 weeks after injection.
Thymocytes are progenitor cells present in the Thymus. These cells are responsible for the
creation of T lymphocytes, otherwise known as T-Cells. This explains why affected Thymocytes
lead to T-Cell affected leukemia.
KRAS in Thymocytes does not actually guarantee that the affected T-Cells formed in the
Thymus. The affected cells could have developed in the bone marrow. This study does also
address this question. To address the location of the affected T-Cells, Bone marrow cells and
Thymocyte cells were isolated and then injected into a second population. Of the second
population, no mice which were injected with the bone marrow cells developed leukemia,
however, mice injected with Thymocyte cells displayed the same phenotype as the first
population that displayed T-cell lymphoblastic leukemia. The conclusion drawn from this
observation is that Thymocyte cells are responsible for the development of T-ALL in the
Thymus and not bone marrow. Subsequent testing confirmed this initial observation.
Although these experiments confirm that KRAS affected cells can cause cancerous
tumors which lead to death, the mice that were affected represent and enriched environment for
HSC or hematopoietic stem cells. In common progenitor cells, that is, without a specifically
enriched environment, the myeloproliferative diseases that were found may not be as abundant or

Val Bejarano
Article Summary
Bio 1615
display advanced progression. More research still needs to be done to completely understand
how RAS mutations can cause certain cancers in a general population.

Val Bejarano
Article Summary
Bio 1615

Bibliography

1. Oncogenic Kras Initiates Leukemia in Hematopoietic Stem Cells by

Amit J. Sabnis1 , Laurene S. Cheung1 , Monique Dail1 , Hio Chung Kang1 , Marianne
Santaguida2 , Michelle L. Hermiston1 , Emmanuelle Passegue 2 , Kevin Shannon1 , Benjamin
S. Braun1*
1 Department of Pediatrics, University of California San Francisco, San Francisco,
California, United States of America,
2 The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research,
University of California San Francisco, San Francisco, California, United States of America