Kinase-inhibitor–insensitive cancer stem cells in chronic myeloid leukemia

2014 ◽  
Vol 14 (3) ◽  
pp. 287-299 ◽  
Author(s):  
Alessandro Morotti ◽  
Cristina Panuzzo ◽  
Carmen Fava ◽  
Giuseppe Saglio
2010 ◽  
Vol 10 (2) ◽  
pp. 111-115 ◽  
Author(s):  
Yaoyu Chen ◽  
Cong Peng ◽  
Con Sullivan ◽  
Dongguang Li ◽  
Shaoguang Li

Leukemia ◽  
2020 ◽  
Vol 34 (10) ◽  
pp. 2635-2647
Author(s):  
Oliver Parting ◽  
Samantha Langer ◽  
Maja Kim Kuepper ◽  
Caroline Wessling ◽  
Shaoguang Li ◽  
...  

Abstract Despite the successes achieved with molecular targeted inhibition of the oncogenic driver Bcr-Abl in chronic myeloid leukemia (CML), the majority of patients still require lifelong tyrosine kinase inhibitor (TKI) therapy. This is primarily caused by resisting leukemic stem cells (LSCs), which prevent achievement of treatment-free remission in all patients. Here we describe the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing Fc gamma receptor IIb (FcγRIIb, CD32b) for being critical in LSC resistance and show that targeting FcγRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcγRIIb upregulation in primary CML stem cells. FcγRIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. FcγRIIb targeting in both a transgenic and retroviral CML mouse model provided in vivo evidence for successful LSC reduction. Subsequently, we identified BTK as a main downstream mediator and targeting the Bcr-Abl-FcγRIIb-BTK axis in primary CML CD34+ cells using ibrutinib, in combination with standard TKI therapy, significantly increased apoptosis in quiescent CML stem cells thereby contributing to the eradication of LSCs.. As a potential curative therapeutic approach, we therefore suggest combining Bcr-Abl TKI therapy along with BTK inhibition.


Leukemia ◽  
2010 ◽  
Vol 24 (9) ◽  
pp. 1545-1554 ◽  
Author(s):  
Y Chen ◽  
C Peng ◽  
C Sullivan ◽  
D Li ◽  
S Li

2012 ◽  
Vol 12 (5) ◽  
pp. 571-596 ◽  
Author(s):  
A. Stefanachi ◽  
F. Leonetti ◽  
O. Nicolotti ◽  
M. Catto ◽  
L. Pisani ◽  
...  

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Naofumi Mukaida ◽  
Yamato Tanabe ◽  
Tomohisa Baba

AbstractA limited subset of human leukemia cells has a self-renewal capacity and can propagate leukemia upon their transplantation into animals, and therefore, are named as leukemia stem cells, in the early 1990’s. Subsequently, cell subpopulations with similar characteristics were detected in various kinds of solid cancers and were denoted as cancer stem cells. Cancer stem cells are presently presumed to be crucially involved in malignant progression of solid cancer: chemoresitance, radioresistance, immune evasion, and metastasis. On the contrary, less attention has been paid to cancer non-stem cell population, which comprise most cancer cells in cancer tissues, due to the lack of suitable markers to discriminate cancer non-stem cells from cancer stem cells. Chronic myeloid leukemia stem cells generate a larger number of morphologically distinct non-stem cells. Moreover, accumulating evidence indicates that poor prognosis is associated with the increases in these non-stem cells including basophils and megakaryocytes. We will discuss the potential roles of cancer non-stem cells in fostering tumor microenvironment, by illustrating the roles of chronic myeloid leukemia non-stem cells including basophils and megakaryocytes in the pathogenesis of chronic myeloid leukemia, a typical malignant disorder arising from leukemic stem cells.


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