PMID- 12893759
OWN - NLM
STAT- MEDLINE
DCOM- 20040105
LR  - 20210206
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 102
IP  - 10
DP  - 2003 Nov 15
TI  - Clonal dominance of chronic myelogenous leukemia is associated with diminished 
      sensitivity to the antiproliferative effects of neutrophil elastase.
PG  - 3786-92
AB  - Clinical observations suggest that in chronic myelogenous leukemia (CML), the 
      Philadelphia chromosome (Ph+) clone has a growth advantage over normal 
      hematopoiesis. Patients with CML have high levels of neutrophil elastase, which 
      has recently been shown to antagonize the action of 
      granulocyte-colony-stimulating factor (G-CSF) and other growth factors. We 
      therefore compared the effect of elastase on the growth of normal and CML 
      progenitor cells. In 10-day suspension cultures of normal or CML CD34+ cells 
      supplemented with G-CSF, stem cell factor (SCF), and granulocyte 
      macrophage-colony-stimulating factor (GM-CSF), CML cells had diminished 
      sensitivity to the growth inhibitory effect of elastase. When equal numbers of 
      CML and normal CD34+ cells were cocultured for 10 days, there was no change in 
      the relative proportions of normal and leukemic cells (measured by fluorescence 
      in situ hybridization [FISH] or flow cytometry). However, when elastase was 
      added, CML cells predominated at the end of the culture period (78% vs 22% with 1 
      microg/mL and 80% vs 20% with 5 microg/mL elastase). CML neutrophils substituted 
      effectively for elastase in suppressing the proliferation of normal CD34+ cells, 
      but this effect was abrogated by serine protease inhibitors. These results 
      suggest that elastase overproduction by the leukemic clone can change the growth 
      environment by digesting growth factors, thereby giving advantage to Ph+ 
      hematopoiesis.
FAU - El-Ouriaghli, Frank
AU  - El-Ouriaghli F
AD  - Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes 
      of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
FAU - Sloand, Elaine
AU  - Sloand E
FAU - Mainwaring, Lori
AU  - Mainwaring L
FAU - Fujiwara, Hiroshi
AU  - Fujiwara H
FAU - Keyvanfar, Keyvan
AU  - Keyvanfar K
FAU - Melenhorst, J Joseph
AU  - Melenhorst JJ
FAU - Rezvani, Katayoun
AU  - Rezvani K
FAU - Sconocchia, Giuseppe
AU  - Sconocchia G
FAU - Solomon, Scott
AU  - Solomon S
FAU - Hensel, Nancy
AU  - Hensel N
FAU - Barrett, A John
AU  - Barrett AJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20030731
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Growth Substances)
RN  - EC 3.4.21.37 (Leukocyte Elastase)
SB  - IM
MH  - Cell Division
MH  - Clone Cells/enzymology/pathology
MH  - Coculture Techniques
MH  - Growth Substances/pharmacology
MH  - Hematopoietic Stem Cells/drug effects
MH  - Humans
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*enzymology/etiology/*pathology
MH  - Leukocyte Elastase/*pharmacology/physiology
MH  - Neoplastic Stem Cells/drug effects/enzymology
MH  - Paracrine Communication
MH  - Tumor Cells, Cultured
EDAT- 2003/08/02 05:00
MHDA- 2004/01/06 05:00
CRDT- 2003/08/02 05:00
PHST- 2003/08/02 05:00 [pubmed]
PHST- 2004/01/06 05:00 [medline]
PHST- 2003/08/02 05:00 [entrez]
AID - S0006-4971(20)50384-4 [pii]
AID - 10.1182/blood-2003-03-0861 [doi]
PST - ppublish
SO  - Blood. 2003 Nov 15;102(10):3786-92. doi: 10.1182/blood-2003-03-0861. Epub 2003 
      Jul 31.