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Disease
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Target Concepts:
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Query: UMLS:C0023473 (
chronic myeloid leukemia
)
18,916
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Leukaemic stem cell (LSC) persistence remains a major obstacle to curing
chronic myeloid leukaemia
(
CML
). The bone morphogenic protein (BMP) pathway is deregulated in
CML
, with altered expression and response to the BMP ligands shown to impact on LSC expansion and behaviour. In this study, we determined whether alterations in the BMP pathway gene signature had any predictive value for therapeutic response by profiling 60
CML
samples at diagnosis from the UK SPIRIT2 trial and correlating the data to treatment response using the 18-month follow-up data. There was significant deregulation of several genes involved in the BMP pathway with ACV1C, INHBA, SMAD7, SNAIL1 and
SMURF2
showing differential expression in relation to response. Therapeutic targeting of
CML
cells using BMP receptor inhibitors, in combination with tyrosine kinase inhibitor (TKI), indicate a synergistic mode of action. Furthermore, dual treatment resulted in altered cell cycle gene transcription and irreversible cell cycle arrest, along with increased apoptosis compared to single agents. Targeting
CML
CD34
+
cells with BMP receptor inhibitors resulted in fewer cell divisions, reduced numbers of CD34
+
cells and colony formation when compared to normal donor CD34
+
cells, both in the presence and absence of BMP4. In an induced pluripotent stem cell (iPSC) model generated from CD34
+
hematopoietic cells, we demonstrate altered cell cycle profiles and dynamics of ALK expression in
CML
-iPSCs in the presence and absence of BMP4 stimulation, when compared to normal iPSC. Moreover, dual targeting with TKI and BMP inhibitor prevented the self-renewal of
CML
-iPSC and increased meso-endodermal differentiation. These findings indicate that transformed stem cells may be more reliant on BMP signalling than normal stem cells. These changes offer a therapeutic window in
CML
, with intervention using BMP inhibitors in combination with TKI having the potential to target LSC self-renewal and improve long-term outcome for patients.
...
PMID:Chronic myeloid leukaemia cells require the bone morphogenic protein pathway for cell cycle progression and self-renewal. 3020 37
