Tisch Cancer Center scientists report that they have developed novel models of the deadliest blood cancer, acute myeloid leukemia (AML), creating a “transformative resource” to study this cancer and eventually its drug response and drug resistance, according to research presented at the annual meeting of the American Association of Cancer Research in Orlando and simultaneously published in Blood Cancer Discovery in an article titled, “Patient-Derived iPSCs Faithfully Represent the Genetic Diversity and Cellular Architecture of Human Acute Myeloid Leukemia” .
“The reprogramming of human AML cells into induced pluripotent stem cell (iPSC) lines could provide new faithful genetic models of AML, but is currently hindered by low success rates and uncertainty about whether iPSC-derived cells resemble their primary counterparts,” wrote the investigators.
Method tailored to cancer cells
“Here we developed a reprogramming method tailored to cancer cells, with which we generated iPSCs from 15 patients representing all major genetic groups of AML. These AML-iPSCs retain genetic fidelity and produce transplantable hematopoietic cells with hallmark phenotypic leukemic features. Critically, single-cell transcriptomics reveal that, upon xenotransplantation, iPSC-derived leukemias faithfully mimic the primary patient-matched xenografts.
“Transplantation of iPSC-derived leukemias capturing a clone and subclone from the same patient allowed us to isolate the contribution of an FLT3-ITD mutation to the AML phenotype. The results and resources reported here can transform basic and preclinical cancer research of AML and other human cancers.”
The finding is the first time that powerful models have been created that are nearly identical to AML found in patients, noted the researchers, who added that these models represent the disease accurately in genetic composition and in disease characteristics found in laboratory cell cultures, animal models, and patients.
This is an important development because AML has only a 29% survival rate, and is a fast-growing cancer. It’s often widespread in the bone marrow and the blood when it’s first discovered in a patient, so being able to study the cancer, its progression, and its response to drugs in accurate and viable cell lines is crucial.
“We show that these models are nearly identical to the leukemias of the patients that they came from and thus are faithful models for acute myeloid leukemia,” said senior author Eirini Papapetrou, MD, PhD, professor of oncological sciences and medicine, hematology, and medical oncology at the Tisch Cancer Institute, a part of the Tisch Cancer Center, and director of the Center for Advancement of Blood Cancer Therapies (CABCT) at the Institute of Regenerative Medicine at Mount Sinai.
“Animal models do not provide accurate genetic models of AML as AML cells from the bone marrow or blood survive poorly outside of the body, and AML cell lines carry many additional genetic and karyotypic abnormalities that make them distinct from primary tumors. Our new models are groundbreaking tools that can uniquely empower leukemia research.”
To create these models, researchers used genetic reprogramming technology to convert blood or bone marrow cells from 15 patients representing all major genetic groups of AML to induced pluripotent stem cells that can mimic different stages of disease progression, from a healthy state to pre-malignancy and finally full-blown leukemia.
The leukemia cells derived from these lines can be transplanted into animal models and create a remarkably similar disease as in the patients.
Many of these lines have been distributed to other researchers, who, along with Papapetrou and her colleagues, will pursue a number of new studies into leukemia pathogenesis and drug responses. A commentary on the significance of Papapetrou’s journal article in Blood Cancer Discovery explains how the study advances the field, both practically and conceptually. (Please note that the commentary is currently only available in PDF format.)
“The large panel of genetically defined iPSC clones…are versatile disease models and important resources for the community,” Sergei Doulatov, PhD, associate professor in the division of hematology at the University of Washington, wrote in the commentary. “This study dispels the notion that leukemias are difficult or impossible to reprogram.”
