c-MPL Is a Candidate Surface Marker and Confers Self-Renewal, Quiescence, Chemotherapy Resistance, and Leukemia Initiation Potential in Leukemia Stem Cells

Abstract

Acute myeloid leukemia (AML) is initiated and maintained by a unique, small subset of leukemia cells known as leukemia stem cells (LSCs). Self-renewal, quiescence, and chemotherapy resistance are key stemness properties of LSCs that are essential for poor clinical responses to conventional therapies. Identifying LSC surface markers and targeting LSCs are important for the development of potential therapies. In this study, application of chemotherapy treatment in AML-ETO9a (AE9a) leukemia mice led to the enrichment of a chemotherapy-resistant cell population identified as Lin c-Kit c-MPL . In addition, this c-MPL-positive cell population within Lin c-Kit leukemia cells included a high percentage of cells in a quiescent state, enhanced colony formation ability, and increased homing efficiency. Serial transplantation demonstrated that Lin c-Kit c-MPL cells displayed a significantly high potential for leukemia initiation. Furthermore, it was demonstrated that in AML patients, c-MPL was expressed on the majority of CD34 leukemia cells and that the proportion of c-MPL cells in CD34 leukemia cells is associated with poor prognosis. Finally, AMM2, an inhibitor of c-MPL, was shown to significantly enhance the survival of AE9a leukemia mice when combined with chemotherapeutic agent. These results indicate that c-MPL is a candidate LSC surface marker that may serve as a therapeutic target for the elimination of LSCs. Stem Cells 2018;36:1685-1696.

<p>The synergistic antileukemic effects of eltrombopag and decitabine in myeloid leukemia cells</p>

“…Concern has been raised in the use of thrombopoietin mimetic agents in MDS and AML patients, as c-MPL is also present on a considerable percentage of myeloid leukemia cells 30,31. Therefore, it is important to identify whether EP stimulates blast cells expressing c-MPL to proliferate.…”

Drug Resistance Mechanisms of Acute Myeloid Leukemia Stem Cells

“…Furthermore, due to the high heterogeneity within and between patients, there is no single indicator to identify LSCs. Data have shown multiple candidate surface markers including CD123 ( 70 ), CD33 ( 71 ), CD96 ( 72 ), TIM-3 ( 73 ), CD44 ( 74 ), CLL-1 ( 75 ), c-MPL ( 76 ), MHDA2 ( 77 ), CD25 and CD32 ( 24 ) that play a significant role in the stemness properties of LSCs. Of these, CD25, CD32, CD123, c-MPL, and MHDA2 are expressed in quiescent human LSCs, and targeting these surface markers may facilitate the removal of dormant LSCs.…”

Characteristics of leukemic stem cells in acute leukemia and potential targeted therapies for their specific eradication

“…Since CD9 is hardly expressed on normal HSCs, it was suggested that this surface marker could be a promising new target for the eradication of LSCs. Second, AML cells positive for c-MPL, a thrombopoietin receptor regulating processes such as self-renewal and HSC proliferation, showed more chemoresistance than the c-MPL negative AML cell population in a mouse leukemic model [ 89 ] . Moreover, the c-MPL+ cells had a higher self-renewal potential and were significantly better at initiating AML in vivo compared to the c-MPL- cell population.…”