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author:("holyoak, T L")
1.  Synergistic effects of proteasome inhibitor carfilzomib in combination with tyrosine kinase inhibitors in imatinib-sensitive and -resistant chronic myeloid leukemia models 
Oncogenesis  2014;3(3):e90-.
The tyrosine kinase inhibitor (TKI) imatinib has transformed the treatment and outlook of chronic myeloid leukemia (CML); however, the development of drug resistance and the persistence of TKI-resistant stem cells remain obstacles to eradicating the disease. Inhibition of proteasome activity with bortezomib has been shown to effectively induce apoptosis in TKI-resistant cells. In this study, we show that exposure to the next generation proteasome inhibitor carfilzomib is associated with a decrease in ERK signaling and increased expression of Abelson interactor proteins 1 and 2 (ABI-1/2). We also investigate the effect of carfilzomib in models of imatinib-sensitive and -resistant CML and demonstrate a potent reduction in proliferation and induction of apoptosis in a variety of models of imatinib-resistant CML, including primitive CML stem cells. Carfilzomib acts synergistically with the TKIs imatinib and nilotinib, even in imatinib-resistant cell lines. In addition, we found that the presence of immunoproteasome subunits is associated with an increased sensitivity to carfilzomib. The present findings provide a rational basis to examine the potential of carfilzomib in combination with TKIs as a potential therapy for CML, particularly in imatinib-resistant disease.
PMCID: PMC3940921  PMID: 24590311
chronic myeloid leukemia; imatinib resistance; tyrosine kinase inhibitor; carfilzomib
2.  Expression of p89c-Mybex9b, an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells 
Blood Cancer Journal  2012;2(5):e71-.
The c-Myb gene encodes the p75c-Myb isoform and less-abundant proteins generated by alternatively spliced transcripts. Among these, the best known is pc-Mybex9b, which contains 121 additional amino acids between exon 9 and 10, in a domain involved in protein–protein interactions and negative regulation. In hematopoietic cells, expression of pc-Mybex9b accounts for 10–15% of total c-Myb; these levels may be biologically relevant because modest changes in c-Myb expression affects proliferation and survival of leukemic cells and lineage choice and frequency of normal hematopoietic progenitors. In this study, we assessed biochemical activities of pc-Mybex9b and the consequences of perturbing its expression in K562 and primary chronic myeloid leukemia (CML) progenitor cells. Compared with p75c-Myb, pc-Mybex9b is more stable and more effective in transactivating Myb-regulated promoters. Ectopic expression of pc-Mybex9b enhanced proliferation and colony formation and reduced imatinib (IM) sensitivity of K562 cells; conversely, specific downregulation of pc-Mybex9b reduced proliferation and colony formation, enhanced IM sensitivity of K562 cells and markedly suppressed colony formation of CML CD34+ cells, without affecting the levels of p75c-Myb. Together, these studies indicate that expression of the low-abundance pc-Mybex9b isoform has an important role for the overall biological effects of c-Myb in BCR/ABL-transformed cells.
PMCID: PMC3366069  PMID: 22829973
transcription factor; oncogene; chronic myeloid leukemia
3.  Is there a cloud in the silver lining for imatinib? 
British Journal of Cancer  2003;88(7):983-987.
PMCID: PMC2376361  PMID: 12671692
CML; imatinib; drug resistance
4.  Previously undetected human hematopoietic cell populations with short-term repopulating activity selectively engraft NOD/SCID-β2 microglobulin–null mice 
Journal of Clinical Investigation  2001;107(2):199-206.
Increasing use of purified or cultured human hematopoietic cells as transplants has revealed an urgent need for better methods to predict the speed and durability of their engraftment potential. We now show that NOD/SCID-β2 microglobulin–null (NOD/SCID-β2m–/–) mice are sequentially engrafted by two distinct and previously unrecognized populations of transplantable human short-term repopulating hematopoietic cells (STRCs), neither of which efficiently engraft NOD/SCID mice. One is predominantly CD34+CD38+ and is myeloid-restricted; the other is predominantly CD34+CD38– and has broader lymphomyeloid differentiation potential. In contrast, the long-term repopulating human cells that generate lymphoid and myeloid progeny in NOD/SCID mice engraft and self-renew in NOD/SCID-β2m–/– mice equally efficiently. In short-term expansion cultures of adult bone marrow cells, myeloid-restricted STRCs were preferentially amplified (greater than tenfold) and, interestingly, both types of STRC were found to be selectively elevated in mobilized peripheral blood harvests. These results suggest an enhanced sensitivity of STRCs to natural killer cell–mediated rejection. They also provide new in vivo assays for different types of human STRC that may help to predict the engraftment potential of clinical transplants and facilitate future investigation of early stages of human hematopoietic stem cell differentiation.
PMCID: PMC199177  PMID: 11160136
5.  Use of plasma ferritin concentration to diagnose iron deficiency in elderly patients. 
Journal of Clinical Pathology  1993;46(9):857-860.
AIMS--To determine a concentration of ferritin below which the possibility of iron deficiency should be considered in elderly patients. METHODS--Consecutive new referrals to a geriatric unit (n = 472) were studied prospectively. Full blood count, ferritin, serum vitamin B12 and red cell folate were measured for all patients. A blood film was assessed independently by three haematologists for features of iron deficiency. For those with ferritin of 12-45 ng/ml, bone marrow aspirates were performed and examined for the presence of stainable iron. When possible, a trial of oral iron was given to those with ferritin of < or = 45 ng/ml and response was determined by re-measurement of full blood count and ferritin after a minimum of three weeks of treatment. RESULTS--Bone marrow examination was performed in 32 patients with ferritin of 12-45 ng/ml, of whom 27 (84%) had absent stainable iron, suggesting that most elderly patients with ferritin in this range have iron deficiency. Compared with those with ferritin of 100-299 ng/ml, in whom iron stores were presumed to be normal, patients with ferritin of 12-45 ng/ml had a significantly lower mean haemoglobin and mean red blood cell volume. Furthermore, patients with ferritin up to 75 ng/ml had a significantly higher mean red cell distribution width, and were more likely to have an iron deficient blood film. CONCLUSION--Iron deficient erythropoiesis can occur in elderly patients with ferritin up to 75 ng/ml. This is much higher than the lower limit of the "normal" range usually quoted for younger subjects; this difference should be taken into account when ferritin concentrations are interpreted in elderly patients.
PMCID: PMC501525  PMID: 8227438

Results 1-6 (6)