Expression of the runt homology domain of RUNX1 disrupts homeostasis of hematopoietic stem cells and induces progression to myelodysplastic syndrome.
Mutations of RUNX1 are detected in patients with myelodysplastic syndrome (MDS). In particular, C-terminal truncation mutations lack a transcription regulatory domain and have increased DNA binding through the runt homology domain. The expression of the runt homology domain, RUNX1(41-214), in mouse hematopoietic cells induced progression to MDS and acute myeloid leukemia. Analysis of premyelodysplastic animals found expansion of c-Kit(+)Sca-1(+)Lin(-) cells and skewed differentiation to myeloid at the expense of the lymphoid lineage. These abnormalities correlate with the phenotype of Runx1-deficient animals, as expected given the reported dominant-negative role of C-terminal mutations over the full-length RUNX1. However, MDS is not observed in Runx1-deficient animals. Gene expression profiling found that RUNX1(41-214) c-Kit(+)Sca-1(+)Lin(-) cells have an overlapping yet distinct gene expression profile from Runx1-deficient animals. Moreover, an unexpected parallel was observed between the hematopoietic phenotype of RUNX1(41-214) and aged animals. Genes deregulated in RUNX1(41-214), but not in Runx1-deficient animals, were inversely correlated with the aging gene signature of HSCs, suggesting that disruption of the expression of genes related to normal aging by RUNX1 mutations contributes to development of MDS. The data presented here provide insights into the mechanisms of development of MDS in HSCs by C-terminal mutations of RUNX1.
Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Shinobu
S
Matsuura
Yukiko
Y
Komeno
Kristen E
KE
Stevenson
Joseph R
JR
Biggs
Kentson
K
Lam
Tingdong
T
Tang
Miao-Chia
MC
Lo
Xiuli
X
Cong
Ming
M
Yan
Donna S
DS
Neuberg
Dong-Er
DE
Zhang
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001853:Bone Marrow / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016000:Cluster Analysis; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007942:Leukemia, Experimental; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism*; D014161:Transduction, Genetic
D050676:Core Binding Factor Alpha 2 Subunit