TY - JOUR
T1 - Characterization of disease-propagating stem cells responsible for myeloproliferative neoplasm–blast phase
AU - Wang, Xiaoli
AU - Rampal, Raajit K.
AU - Hu, Cing Siang
AU - Tripodi, Joseph
AU - Farnoud, Noushin
AU - Petersen, Bruce
AU - Rossi, Michael R.
AU - Patel, Minal
AU - McGovern, Erin
AU - Najfeld, Vesna
AU - Iancu-Rubin, Camelia
AU - Lu, Min
AU - Davis, Andrew
AU - Kremyanskaya, Marina
AU - Weinberg, Rona Singer
AU - Mascarenhas, John
AU - Hoffman, Ronald
N1 - Funding Information:
This work was supported by a grant from the Incyte Corporation (XW and JM). NGS analysis was supported by the MPN-RC (P01 CA108671) (RH).
Publisher Copyright:
© 2022, Wang et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2022/4/22
Y1 - 2022/4/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85128698482&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.156534
DO - 10.1172/jci.insight.156534
M3 - Article
C2 - 35259128
AN - SCOPUS:85128698482
SN - 2379-3708
VL - 7
JO - JCI insight
JF - JCI insight
IS - 8
M1 - e156534
ER -