scholarly journals Merit of the paper "PP2A inhibition sensitize cancer stem cells to ABL tyrosine kinase inhibition in BCR-ABL human leukemia" authored by Lai et al. [Science Translational Medicine (2019) Vol. 11, Issue 501, eaau0416, DOI: 10.1126/scitranslmed.aau0416]

2020 ◽  
Author(s):  
H.Y. Lim Tung ◽  
H.Y. Lim Tung ◽  
H.Y. Lim Tung ◽  
H.Y. Lim Tung ◽  
H.Y. Lim Tung ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Enzyme Regulation ◽  
Human Leukemia ◽  
Abl Tyrosine Kinase ◽  
Important Principle ◽  
Double Edge ◽  
Double Edge Sword ◽  
Blast Cells

The paper by Lai et al. [1] showed that inhibition of PP-2A with LB100 or LB102 in conjunction with Tyrosine kinase Inhibitors (TKIs) was effective at targeting BCR-ABL + blast cells and insensitive leukemic stem cells (LSCs). Perotti et al. [2] has severely criticised the paper by Lai et al [2]. However, Perotti et al. [2] has failed to appreciate an important principle of the role of PP-2A as a tumor suppressor and its regulation in the cell, namely that in general, PP-2A dephosphoryltes and inactivates enzymes and proteins that upregulate cell proliferation, cell survival, tumorigenic and metastasizing pathways but with a limited number of of enzymes and proteins, PP-2A acts to upregulate them. Thus, PP-2A is a double-edge sword and modulation of its activity must be calibrated empirically. Also, Perotti et al. [2] has misunderstood an important principle of enzyme regulation, namely that PP-2A is regulated by inhibitory and activating molecules and not through "targeting proteins" which has not been scientifically verified. It is submitted that the paper by Lai et al. [1] has strong merit as it shows for the first time that an inhibitor of PP-2A can synergize with a TKI.

scholarly journals Comment on “PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL human leukemia”

2019 ◽  
Vol 11 (501) ◽  
pp. eaau0416 ◽  
Author(s):  
Danilo Perrotti ◽  
Anupriya Agarwal ◽  
Claire M. Lucas ◽  
Goutham Narla ◽  
Paolo Neviani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Human Leukemia ◽  
Abl Tyrosine Kinase ◽  
Induced Apoptosis

LB100 does not sensitize CML stem cells to tyrosine kinase inhibitor–induced apoptosis.

PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL+human leukemia

2018 ◽  
Vol 10 (427) ◽  
pp. eaan8735 ◽  
Author(s):  
Damian Lai ◽  
Min Chen ◽  
Jiechuang Su ◽  
Xiaohu Liu ◽  
Katharina Rothe ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Human Leukemia ◽  
Abl Tyrosine Kinase

Down-Modulation of P210bcr/abl Induces Apoptosis/Differentiation in K562 Leukemic Blast Cells

1997 ◽  
Vol 83 (4) ◽  
pp. 756-761 ◽  
Author(s):  
Arunkumar B. Deora ◽  
Michelle B. Miranda ◽  
S.G. Anand Rao
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
Leukemic Blast ◽  
Tyrosine Kinase Activity ◽  
Abl Tyrosine Kinase ◽  
Blast Cells ◽  
Induced Apoptosis

Aims and background K562 cells are growth factor independent and neither function as stem cells nor differentiate into functional end cells. They are blast cells. There is evidence that the constitutively expressed bcr-abl tyrosine kinase might be responsible for the maintenance of the blast state of CML cells. We have studied the effect of two tyrosine kinase inhibitors, quercetin and genistein, on K562 cells. Methods K562 cells were treated with quercetin/genistein for a period of 72 hrs and then subjected to staining for apoptosis and erythroid differentiation and Western blotting with c-abl and phosphotyrosine monoclonal antibodies. Results The IC50 value was found to be 9.2 μg/ml for quercetin and 11.8 μg/ml for genistein. Quercetin-treated cells did not show any differentiation but showed 68% apoptosis as compared to 7% in control. Genistein-treated cells showed 16% apoptosis and 15% erythroid differentiation. Quercetin reduced the level of p210 by 74% and its phosphotyrosine content by 67.6%. Genistein reduced p210 by 77.8% and its phosphotyrosine content by 16%. Conclusion Both quercetin and genistein are able to down-modulate the tyrosine kinase activity of p210 as well as bring about a decrease in the content of the protein with different effects: quercetin induced apoptosis while genistein brought about both differentiation and apoptosis.

Tyrosine Kinase Inhibitors in Pulmonary Arterial Hypertension: A Double-Edge Sword?

2013 ◽  
Vol 34 (05) ◽  
pp. 714-724 ◽  
Author(s):  
Laurent Godinas ◽  
Christophe Guignabert ◽  
Andrei Seferian ◽  
Frederic Perros ◽  
Emmanuel Bergot ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Tyrosine Kinase ◽  
Arterial Hypertension ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Double Edge ◽  
Double Edge Sword ◽  
Pulmonary Arterial

Growth Factor Independent 1b (Gfi1b) Is Highly Expressed in Human CML and Accelerates p210BCR-ABL Induced Leukemia in Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1023-1023
Author(s):  
Lothar Vassen ◽  
Daniel G. Tenen ◽  
Bert A. van der Reijden ◽  
Ulrich Duehrsen ◽  
Tarik Moroy ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Human Leukemia ◽  
Hematopoietic Stem ◽  
Long Term Treatment

Abstract Chronic myeloid leukemia (CML) is one of the most frequent leukemic diseases and invariably associated with a reciprocal t(9;22) translocation which creates a juxtaposition of the BCR and ABL genes to form the p230-, p190- or p210BCR-ABL constitutively active tyrosine kinases. This constitutive tyrosine kinase activity is the cause of CML and other leukemic diseases. CML is very efficiently treated with small molecule tyrosine kinase inhibitors, but CML is a stem cell initiated disease and surprisingly the leukemic stem cells cannot be eradicated by tyrosine kinase inhibitor treatment, resulting in a high risk of the development of therapy resistance. To design more successful therapies, it is primordial to understand the molecular mechanisms underlying this disease. Here we show that growth factor independent 1b (Gfi1b), also translocated in CML, is strongly induced in peripheral blood mononuclear cells (PBMCs) in patients with chronic- or acute myeloid leukemia (AML) as well as in patients suffering from myeloprolifarative syndrome (MPS) or B-lymphoblastic leukemia (B-ALL). Gfi1b is a transcriptional repressor essential for erythroid- and megacaryocytic cells, but also expressed in hematopoietic stem cells, early myeloid precursors and mature myeloid cells in peripheral blood. Interestingly, the expression of Gfi1b is further induced by long term treatment with tyrosine kinase inhibitors like Glivec, although the patients are phenotypically in remission. Additionally we describe a new splice variant of Gfi1b which is overrepresented in CML, AML and B-ALL, but not in MPS. Using a mouse model system we demonstrate, that Gfi1b strongly accelerates p210BCR-ABL induced leukemogenesis. We further show that Gfi1b inhibits the activity of PU.1, a key molecule in hematopoiesis and repressor of leukemogenesis. Our findings bear considerable significance with regard to the role of Gfi1b as an oncogene in human leukemia and to its possible value as a new target for leukemia therapy.

scholarly journals Response to Comment on “PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL+ human leukemia”

2019 ◽  
Vol 11 (501) ◽  
pp. eaav0819 ◽  
Author(s):  
Damian Lai ◽  
Min Chen ◽  
Jiechuang Su ◽  
Xiaohu Liu ◽  
Katharina Rothe ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cancer Stem Cells ◽  
Progenitor Cells ◽  
Kinase Inhibitors ◽  
Bone Marrow Cells ◽  
Chronic Phase ◽  
Human Leukemia ◽  
Abl Tyrosine Kinase ◽  
Stem And Progenitor Cells

LB100 sensitizes resistant chronic phase CML stem and progenitor cells to TKIs and spares healthy bone marrow cells.

scholarly journals Specificity of dermatological adverse events of BCR-ABL tyrosine kinase inhibitors and their effect on quality of life of patients with chronic myeloid leukemia

2020 ◽  
pp. 72-76
Author(s):  
E. A. Shatokhina ◽  
A. G. Turkina ◽  
E. Yu. Chelysheva ◽  
O. A. Shukhov ◽  
A. N. Petrova ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Maculopapular Rash ◽  
Abl Tyrosine Kinase

Introduction. BCR-ABL tyrosine kinase inhibitors are currently used to successfully treat chronic myeloid leukemia (CML). Drug therapy is carried out in a continuous daily mode throughout the patient’s life. Treatment with this group of drugs is associated with specific dermatological adverse events (dAE), which can lead to a change in the regimen of effective, vital therapy for CML patients.Purpose. To study the characteristics of dermatological adverse events, the severity and influence on the quality of life of BCR-ABL tyrosine kinase inhibitors.Patients and methods. The observational study included 93 patients. The clinical manifestations of dAE, their severity were evaluated, their photographs and pathomorphological studies of skin biopsy samples were performed, cases of dose reduction or drug withdrawal due to dAE were recorded. The quality of life of patients with dAE was determined based on the assessment of the dermatological index of quality of life.Results. Imatinib therapy was accompanied by a maculopapular rash in 43.3 % of patients, nilotinib caused follicular keratosis in 12.9 % of patients. In 3.2 % of patients, dasatinib caused hyperpigmentation, in 2.2 % of patients lichenoid rashes of the II degree occurred during treatment with bosutinib. Ponatinib treatment was followed by dAE in 9.7 % of patients. All dAE have an impact on the quality of life of patients, but the maculopapular rash and dyskeratotic changes are most pronounced. In a pathomorphological study, these dAE have specific features corresponding to immuno-mediated dermatitis.Conclusions. The most frequent and pronounced dAE that significantly affect the quality of life of patients with CML are a maculopapular rash and dyskeratotic skin changes: psoriasiform and lichenoid dermatitis. Clinical and pathomorphological characteristics of skin reactions make it possible in the future to determine effective methods of supportive therapy for dAE.

Prognostic factors of chronic myeloid leukaemia

2020 ◽  
pp. 63-78
Author(s):  
Michele Baccarani ◽  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Francesca Palandri ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Risk Stratification ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
First Line ◽  
Abl Tyrosine Kinase ◽  
Baseline Characteristics ◽  
Kinase Domain Mutations

Two decades following the successful introduction of the ABL tyrosine kinase inhibitors in clinics for the treatment of patients with chronic myeloid leukaemia (CML), the principal objective of treatment in chronic phase (CP) is survival, preferably without life-long therapy. In tandem, the methodology and tools for assessing the prognosis of the newly diagnosed patient with CML in CP has evolved substantially. Prior to the era of tyrosine kinase inhibitors (TKIs), risk assessment depended more on the response to treatment than on baseline characteristics. The Sokal score, introduced in 1984, was the first one dividing patients into three risk categories based on a mathematical formula taking into account the patient’s age, and baseline characteristics like blast cell count, spleen size, and platelet count. This, and the several other subsequent risk stratification methods developed during the chemotherapy and interferon-alpha era, have remained useful in the first-line TKI treatment, and identifies a variable proportion of high-risk patients with lower response rates and worse outcomes. In second line, the most important risk factors are the absence of haematologic or cytogenetic response on first line, the presence of hematologic toxicity the development of additional cytogenetic abnormities (ACA), and the development of BCR-ABL1 kinase domain mutations. In this chapter, we address the prognosis of CML and the various methods for risk stratification.

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