ABSTRACT
Cancer-derived iPSCs have provided valuable insight into oncogenesis, but human cancer cells can often be difficult to reprogram, especially in cases of complex genetic abnormalities. Here we report, to our knowledge, the first successful generation of an iPSC line from a human immortalized acute myeloid leukemia (AML) cell line, the cell line HL-60. This iPSC line retains a majority of the leukemic genotype and displays defects in myeloid differentiation, thus providing a tool for modeling and studying AML.
Subject(s)
Induced Pluripotent Stem Cells , Leukemia, Myeloid, Acute , Cell Differentiation , HL-60 Cells , Hematopoiesis , Humans , Leukemia, Myeloid, Acute/geneticsABSTRACT
Reliable approaches to identify stem cell mechanisms that mediate aggressive cancer could have great therapeutic value, based on the growing evidence of embryonic signatures in metastatic cancers. However, how to best identify and target stem-like mechanisms aberrantly acquired by cancer cells has been challenging. We harnessed the power of reprogramming to examine GRP78, a chaperone protein generally restricted to the endoplasmic reticulum in normal tissues, but which is expressed on the cell surface of human embryonic stem cells and many cancer types. We have discovered that (1) cell surface GRP78 (sGRP78) is expressed on iPSCs and is important in reprogramming, (2) sGRP78 promotes cellular functions in both pluripotent and breast cancer cells (3) overexpression of GRP78 in breast cancer cells leads to an induction of a CD24-/CD44+ tumor initiating cell (TIC) population (4) sGRP78+ breast cancer cells are enriched for stemness genes and appear to be a subset of TICs (5) sGRP78+ breast cancer cells show an enhanced ability to seed metastatic organ sites in vivo. These collective findings show that GRP78 has important functions in regulating both pluripotency and oncogenesis, and suggest that sGRP78 marks a stem-like population in breast cancer cells that has increased metastatic potential in vivo.
Subject(s)
Cell Differentiation , Cell Self Renewal , Heat-Shock Proteins/metabolism , Neoplastic Stem Cells/metabolism , Animals , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Transformation, Neoplastic , Cellular Reprogramming , Endoplasmic Reticulum Chaperone BiP , Female , HEK293 Cells , Heat-Shock Proteins/antagonists & inhibitors , Heat-Shock Proteins/genetics , Humans , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Mice , Mice, Knockout , Neoplastic Stem Cells/cytology , RNA Interference , RNA, Small Interfering/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Transplantation, HeterologousABSTRACT
Using iPSCs to study cancer has been complicated by the fact that many cancer cells are difficult to reprogram, which has been attributed to the genomic abnormalities present. Acute Myeloid Leukemia (AML) is a complex disease that presents with various types of genomic aberrations that affect prognosis. Here we reprogrammed CD34+ cells from an AML patient containing a rare der(7)t(7;13) translocation associated with poor prognosis, who had relapsed and was refractory to current treatments. The generated AML-iPSCs displayed normal karyotypes and myeloid differentiation potential. These findings have implications for modeling and treating AML disease.
Subject(s)
Bone Marrow/pathology , Cell Differentiation , Drug Resistance, Neoplasm , Induced Pluripotent Stem Cells/pathology , Leukemia, Myeloid, Acute/pathology , Myeloid Cells/pathology , Neoplasm Recurrence, Local/pathology , Aged , Humans , Karyotype , Male , Tumor Cells, CulturedABSTRACT
Three recent studies analyzing large-scale collections of human induced pluripotent stem cell lines provide valuable insight into how genetic regulatory variation affects cellular and molecular traits.