Characterization of disease-propagating stem cells responsible for myeloproliferative neoplasm–blast phase Journal Article
| Authors: | Wang, X.; Rampal, R. K.; Hu, C. S.; Tripodi, J.; Farnoud, N.; Petersen, B.; Rossi, M. R.; Patel, M.; McGovern, E.; Najfeld, V.; Iancu-Rubin, C.; Lu, M.; Davis, A.; Kremyanskaya, M.; Weinberg, R. S.; Mascarenhas, J.; Hoffman, R. |
| Article Title: | Characterization of disease-propagating stem cells responsible for myeloproliferative neoplasm–blast phase |
| Abstract: | Chronic myeloproliferative neoplasms (MPN) frequently evolve to a blast phase (BP) that is almost uniformly resistant to induction chemotherapy or hypomethylating agents. We explored the functional properties, genomic architecture, and cell of origin of MPN-BP initiating cells (IC) using a serial NSG mouse xenograft transplantation model. Transplantation of peripheral blood mononuclear cells (MNC) from 7 of 18 patients resulted in a high degree of leukemic cell chimerism and recreated clinical characteristics of human MPN-BP. The function of MPN-BP ICs was not dependent on the presence of JAK2V617F, a driver mutation associated with the initial underlying MPN. By contrast, multiple MPN-BP IC subclones coexisted within MPN-BP MNCs characterized by different myeloid malignancy gene mutations and cytogenetic abnormalities. MPN-BP ICs in 4 patients exhibited extensive proliferative and self-renewal capacity, as demonstrated by their ability to recapitulate human MPN-BP in serial recipients. These MPN-BP IC subclones underwent extensive continuous clonal competition within individual xenografts and across multiple generations, and their subclonal dynamics were consistent with functional evolution of MPN-BP IC. Finally, we show that MPN-BP ICs originate from not only phenotypically identified hematopoietic stem cells, but also lymphoid-myeloid progenitor cells, which were each characterized by differences in MPN-BP initiating activity and self-renewal capacity. © 2022, Wang et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. |
| Keywords: | controlled study; myeloproliferative disorders; human cell; somatic mutation; genetics; mutation; myeloproliferative disorder; clinical feature; disease course; nonhuman; cell proliferation; animal cell; mouse; phenotype; animal; animals; mice; animal tissue; cell function; animal experiment; animal model; evolution; pathology; cell population; stem cell; chimera; chromosome aberration; mononuclear cell; leukocytes, mononuclear; leukemia cell; cancer stem cell; hematopoietic stem cells; hematopoietic stem cell; genetic disorder; lymphoid progenitor cell; myeloid progenitor cell; myeloproliferative neoplasm; blast cell crisis; cloning; clinical outcome; blast crisis; cell self-renewal; cytogenetic abnormality; blast phase; humans; human; article; clonal competition; disease propagating stem cell; subclonal dynamics |
| Journal Title: | JCI Insight |
| Volume: | 7 |
| Issue: | 8 |
| ISSN: | 2379-3708 |
| Publisher: | Amer Soc Clinical Investigation Inc |
| Date Published: | 2022-04-22 |
| Start Page: | e156534 |
| Language: | English |
| DOI: | 10.1172/jci.insight.156534 |
| PUBMED: | 35259128 |
| PROVIDER: | scopus |
| PMCID: | PMC9089790 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2022 -- Source: Scopus |
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