scholarly journals Chronic myelomonocytic leukemia patients with RAS pathway mutations show high in vitro myeloid colony formation in the absence of exogenous growth factors

Leukemia ◽  
2016 ◽  
Vol 30 (11) ◽  
pp. 2280-2281 ◽  
Author(s):  
K Geissler ◽  
E Jäger ◽  
A Barna ◽  
T Alendar ◽  
E Ljubuncic ◽  
...  
Keyword(s):  
Growth Factors ◽  
Colony Formation ◽  
Chronic Myelomonocytic Leukemia ◽  
Ras Pathway ◽  
Exogenous Growth ◽  
Exogenous Growth Factors ◽  
Myelomonocytic Leukemia

scholarly journals Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia—A Retrospective Analysis in 337 Patients

2020 ◽  
Vol 21 (8) ◽  
pp. 3025 ◽  
Author(s):  
Klaus Geissler ◽  
Eva Jäger ◽  
Agnes Barna ◽  
Michael Gurbisz ◽  
Temeida Graf ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Treatment Strategies ◽  
Colony Growth ◽  
Chronic Myelomonocytic Leukemia ◽  
Peripheral Blood Mononuclear ◽  
Ras Pathway ◽  
Increased Risk ◽  
Functional Analyses ◽  
Myelomonocytic Leukemia

Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, n = 236) and with (B, n = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, n = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% (p < 0.0001), and of high colony growth (≥20/105 peripheral blood mononuclear cells) 31%, 44%, and 80% (p < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies.

scholarly journals Interleukin-6 and granulocyte-macrophage colony-stimulating factor are candidate growth factors for chronic myelomonocytic leukemia cells

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1472-1476 ◽  
Author(s):  
MP Everson ◽  
CB Brown ◽  
MB Lilly
Keyword(s):  
Growth Factors ◽  
Interleukin 6 ◽  
Myeloid Leukemia ◽  
Chronic Myelomonocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Autocrine Growth ◽  
Gm Csf ◽  
Myelomonocytic Leukemia

Previous studies suggest that malignant cells from some patients with myeloid leukemias produce colony-stimulating factors (CSFs) that can function as autocrine growth factors in vitro. We have examined the roles of interleukin-6 (IL-6) and granulocyte-macrophage CSF (GM-CSF) in the proliferation of myeloid leukemia cells. IL-6 activity was assessed in conditioned medium (CM) from myeloid leukemia cell cultures or cell lysates using IL-6-dependent KD83 and 7TD1 murine cell lines. Media conditioned by cells from patients with chronic myelomonocytic leukemia (CMMoL), but not by normal monocytes, chronic myelogenous leukemia (CML), or acute myelogenous leukemia (AML) cells, contained substantial levels (50 to 1,000 U/10(6) cells) of IL-6. The IL-6 content of CM correlated directly with donor peripheral blood WBC count. CM from two of five CMMoL samples also contained greater than 350 pg/mL GM-CSF. Moreover, CMMoL cells spontaneously formed colonies in semisolid medium. CMMoL colony formation could be partially inhibited by antibodies to IL-6 or GM-CSF, whereas combination of these antibodies gave additive, and nearly complete (greater than 93%), inhibition of spontaneous colony formation. Cell lysates from uncultured CMMoL cells from one patient contained abundant GM-CSF protein but no detectable IL-6. These data suggest that IL-6 and GM-CSF act in vitro as autocrine growth factors for CMMoL cells, and that CMMoL cells in vivo may represent a GM-CSF-dependent autocrine growth system.

scholarly journals Exogenous growth factors bFGF, EGF and HGF do not influence viability and phenotype of V600EBRAF melanoma cells and their response to vemurafenib and trametinib in vitro

PLoS ONE ◽  
2017 ◽  
Vol 12 (8) ◽  
pp. e0183498 ◽  
Author(s):  
Izabela Zalesna ◽  
Marta Osrodek ◽  
Mariusz L. Hartman ◽  
Michal Rozanski ◽  
Malgorzata Sztiller-Sikorska ◽  
...  
Keyword(s):  
Growth Factors ◽  
Melanoma Cells ◽  
Exogenous Growth ◽  
Exogenous Growth Factors

scholarly journals Molecular Basis and Clinical Application of Growth-Factor-Independent In Vitro Myeloid Colony Formation in Chronic Myelomonocytic Leukemia

2020 ◽  
Vol 21 (17) ◽  
pp. 6057
Author(s):  
Klaus Geissler ◽  
Eva Jäger ◽  
Agnes Barna ◽  
Michael Gurbisz ◽  
Temeida Graf ◽  
...  
Keyword(s):  
Growth Factor ◽  
Colony Formation ◽  
Molecular Basis ◽  
Strong Predictor ◽  
Chronic Myelomonocytic Leukemia ◽  
Molecular Profile ◽  
Molecular Features ◽  
Increased Risk ◽  
Myelomonocytic Leukemia

We have originally reported that colony-forming units granulocyte/macrophage (CFU-GM) formation is an in vitro feature of chronic myelomonocytic leukemia (CMML) and a strong predictor for short survival. Elucidation of the molecular basis underlying this in vitro phenomenon could be helpful to define molecular features that predict inferior outcome in patients. We studied the correlation between the mutational landscape and spontaneous colony formation in 164 samples from 125 CMML patients. As compared to wildtype samples, spontaneous in vitro CFU-GM formation was significantly increased in samples containing mutations in NRAS, CBL and EZH2 that were confirmed as independent stimulatory factors by multiple regression analysis. Inducible expression of mutated RAS but not JAK2 was able to induce growth factor independence of Ba/F3 cells. Whereas high colony CFU-GM growth was a strong unfavorable parameter for survival (p < 0.00001) and time to transformation (p = 0.01390), no single mutated gene had the power to significantly predict for both outcome parameters. A composite molecular parameter including NRAS/CBL/EZH2, however, was predictive for inferior survival (p = 0.00059) as well as for increased risk of transformation (p = 0.01429). In conclusion, we show that the composite molecular profile NRAS/CBL/EZH2 derived from its impact on spontaneous in vitro myeloid colony formation improves the predictive power over single molecular parameters in patients with CMML.

scholarly journals Effects of recombinant human GM-CSF on proliferation of clonogenic cells in acute myeloblastic leukemia

Blood ◽  
1986 ◽  
Vol 67 (5) ◽  
pp. 1448-1453 ◽  
Author(s):  
JD Griffin ◽  
D Young ◽  
F Herrmann ◽  
D Wiper ◽  
K Wagner ◽  
...  
Keyword(s):  
Growth Factors ◽  
Acute Myeloblastic Leukemia ◽  
Small Subset ◽  
Growth Promoter ◽  
Tumor Cell Lines ◽  
Gm Csf ◽  
Exogenous Growth ◽  
Exogenous Growth Factors ◽  
Stimulation Of

Abstract Proliferation of acute myeloblastic leukemia (AML) cells in vitro is limited in most cases to a small subset of blasts that have several properties of stem cells. These leukemic colony-forming cells (AML-CFU) generally require addition of exogenous growth factors for proliferation in agar or methylcellulose. These factors can be supplied by media conditioned by phytohemagglutinin-stimulated normal leukocytes or by CSF-secreting tumor cell lines. However, the exact factor or factors required for stimulation of AML-CFU growth have not been defined. We compared the AML-CFU stimulatory activity of a human recombinant GM-CSF with that of GCT-CM, Mo-CM, and the PHA-leukocyte feeder system in 15 cases of AML. In each of the 12 cases that required exogenous growth factors for maximum AML-CFU growth, recombinant GM-CSF could replace either GM-CSF or Mo-CM, and could partially replace the PHA-leukocyte feeder system. These results indicate that this GM-CSF is a growth promoter of AML-CFU in these culture systems.

scholarly journals Interleukin-6 and granulocyte-macrophage colony-stimulating factor are candidate growth factors for chronic myelomonocytic leukemia cells

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1472-1476 ◽  
Author(s):  
MP Everson ◽  
CB Brown ◽  
MB Lilly
Keyword(s):  
Growth Factors ◽  
Interleukin 6 ◽  
Myeloid Leukemia ◽  
Chronic Myelomonocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Autocrine Growth ◽  
Gm Csf ◽  
Myelomonocytic Leukemia

Abstract Previous studies suggest that malignant cells from some patients with myeloid leukemias produce colony-stimulating factors (CSFs) that can function as autocrine growth factors in vitro. We have examined the roles of interleukin-6 (IL-6) and granulocyte-macrophage CSF (GM-CSF) in the proliferation of myeloid leukemia cells. IL-6 activity was assessed in conditioned medium (CM) from myeloid leukemia cell cultures or cell lysates using IL-6-dependent KD83 and 7TD1 murine cell lines. Media conditioned by cells from patients with chronic myelomonocytic leukemia (CMMoL), but not by normal monocytes, chronic myelogenous leukemia (CML), or acute myelogenous leukemia (AML) cells, contained substantial levels (50 to 1,000 U/10(6) cells) of IL-6. The IL-6 content of CM correlated directly with donor peripheral blood WBC count. CM from two of five CMMoL samples also contained greater than 350 pg/mL GM-CSF. Moreover, CMMoL cells spontaneously formed colonies in semisolid medium. CMMoL colony formation could be partially inhibited by antibodies to IL-6 or GM-CSF, whereas combination of these antibodies gave additive, and nearly complete (greater than 93%), inhibition of spontaneous colony formation. Cell lysates from uncultured CMMoL cells from one patient contained abundant GM-CSF protein but no detectable IL-6. These data suggest that IL-6 and GM-CSF act in vitro as autocrine growth factors for CMMoL cells, and that CMMoL cells in vivo may represent a GM-CSF-dependent autocrine growth system.

scholarly journals Effects of recombinant human GM-CSF on proliferation of clonogenic cells in acute myeloblastic leukemia

Blood ◽  
1986 ◽  
Vol 67 (5) ◽  
pp. 1448-1453 ◽  
Author(s):  
JD Griffin ◽  
D Young ◽  
F Herrmann ◽  
D Wiper ◽  
K Wagner ◽  
...  
Keyword(s):  
Growth Factors ◽  
Acute Myeloblastic Leukemia ◽  
Small Subset ◽  
Growth Promoter ◽  
Tumor Cell Lines ◽  
Gm Csf ◽  
Exogenous Growth ◽  
Exogenous Growth Factors ◽  
Stimulation Of

Proliferation of acute myeloblastic leukemia (AML) cells in vitro is limited in most cases to a small subset of blasts that have several properties of stem cells. These leukemic colony-forming cells (AML-CFU) generally require addition of exogenous growth factors for proliferation in agar or methylcellulose. These factors can be supplied by media conditioned by phytohemagglutinin-stimulated normal leukocytes or by CSF-secreting tumor cell lines. However, the exact factor or factors required for stimulation of AML-CFU growth have not been defined. We compared the AML-CFU stimulatory activity of a human recombinant GM-CSF with that of GCT-CM, Mo-CM, and the PHA-leukocyte feeder system in 15 cases of AML. In each of the 12 cases that required exogenous growth factors for maximum AML-CFU growth, recombinant GM-CSF could replace either GM-CSF or Mo-CM, and could partially replace the PHA-leukocyte feeder system. These results indicate that this GM-CSF is a growth promoter of AML-CFU in these culture systems.

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