scholarly journals Pharmacogenomics of Impaired Tyrosine Kinase Inhibitor Response: Lessons Learned From Chronic Myelogenous Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Meike Kaehler ◽  
Ingolf Cascorbi
Keyword(s):  
Tyrosine Kinase ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Survival Rates ◽  
Lessons Learned ◽  
Myelogenous Leukemia ◽  
Anti Cancer ◽  
Tki Resistance

The use of small molecules became one key cornerstone of targeted anti-cancer therapy. Among them, tyrosine kinase inhibitors (TKIs) are especially important, as they were the first molecules to proof the concept of targeted anti-cancer treatment. Since 2001, TKIs can be successfully used to treat chronic myelogenous leukemia (CML). CML is a hematologic neoplasm, predominantly caused by reciprocal translocation t(9;22)(q34;q11) leading to formation of the so-called BCR-ABL1 fusion gene. By binding to the BCR-ABL1 kinase and inhibition of downstream target phosphorylation, TKIs, such as imatinib or nilotinib, can be used as single agents to treat CML patients resulting in 80 % 10-year survival rates. However, treatment failure can be observed in 20-25 % of CML patients occurring either dependent or independent from the BCR-ABL1 kinase. Here, we review approved TKIs that are indicated for the treatment of CML, their side effects and limitations. We point out mechanisms of TKI resistance focusing either on BCR-ABL1-dependent mechanisms by summarizing the clinically observed BCR-ABL1-mutations and their implications on TKI binding, as well as on BCR-ABL1-independent mechanisms of resistances. For the latter, we discuss potential mechanisms, among them cytochrome P450 implications, drug efflux transporter variants and expression, microRNA deregulation, as well as the role of alternative signaling pathways. Further, we give insights on how TKI resistance could be analyzed and what could be learned from studying TKI resistance in CML in vitro.

scholarly journals Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hu Lei ◽  
Han-Zhang Xu ◽  
Hui-Zhuang Shan ◽  
Meng Liu ◽  
Ying Lu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Tki Resistance

AbstractIdentifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.

scholarly journals Selection of myeloid progenitors lacking BCR/ABL mRNA in chronic myelogenous leukemia patients after in vitro treatment with the tyrosine kinase inhibitor genistein

Blood ◽  
1996 ◽  
Vol 88 (8) ◽  
pp. 3091-3100 ◽  
Author(s):  
C Carlo-Stella ◽  
G Dotti ◽  
L Mangoni ◽  
E Regazzi ◽  
D Garau ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Continuous Exposure ◽  
Rt Pcr ◽  
Hematopoietic Progenitors ◽  
Colony Forming Unit

Chronic myelogenous leukemia (CML) is a clonal disorder of the hematopoietic stem cell characterized by a chimeric BCR/ABL gene giving rise to a 210-kD fusion protein with dysregulated tyrosine kinase activity. We investigated the effect of genistein, a protein tyrosine kinase inhibitor, on the in vitro growth of CML and normal marrow-derived multi-potent (colony-forming unit-mix [CFU-Mix]), erythroid (burst-forming unit-erythroid [BFU-E]), and granulocyte-macrophage (colony-forming unit-granulocyte-macrophage [CFU-GM]) hematopoietic progenitors. Continuous exposure of CML and normal marrow to genistein induced a statistically significant and dose-dependent suppression of colony formation. Genistein doses causing 50% inhibition of CML and normal progenitors were not significantly different for CFU-Mix (27 mumol/L v 23 mumol/L), BFU-E (31 mumol/L v 29 mumol/L), and CFU-GM (40 mumol/L v 32 mumol/L v 32 mumol/L). Preincubation of CML and normal marrow with genistein (200 mumol/ L for 1 to 18 hours) induced a time-dependent suppression of progenitor cell growth, while sparing a substantial proportion of long-term culture-initiating cells (LTC-IC) from CML (range, 91% +/- 9% to 32% +/- 3%) and normal marrow (range, 85% +/- 8% to 38% +/- 9%). Analysis of individual CML colonies for the presence of the hybrid BCR/ABL mRNA by reverse transcription-polymerase chain reaction (RT-PCR) showed that genistein treatment significantly reduced the mean +/- SD percentage of marrow BCR/ABL+ progenitors both by continuous exposure (76% +/- 18% v 24% +/- 12%, P ‼ or = .004) or preincubation (75% +/- 16% v 21% +/- 10%, P ‼ or = .002) experiments. Preincubation with genistein reduced the percentage of leukemic LTC-IC from 87% +/- 12% to 37% +/- 12% (P ‼ or = .003). Analysis of individual colonies by cytogenetics and RT-PCR confirmed that genistein-induced increase in the percentage of nonleukemic progenitors was not due to suppression of BCR/ABL transcription. Analysis of nuclear DNA fragmentation by DNA gel electrophoresis and terminal deoxynucleotidyl transferase assay showed that preincubation of CML mononuclear and CD34+ cells with genistein induced significant evidence of apoptosis. These observations show that genistein is capable of (1) exerting a strong antiproliferative effect on CFU-Mix, BFU-E, and CFU-GM while sparing the more primitive LTC-IC and (2) selecting benign hematopoietic progenitors from CML marrow, probably through an apoptotic mechanism.

USP47 Is a New Target in Chronic Myelogenous Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1572-1572
Author(s):  
Hu Lei ◽  
Chunmin Ma ◽  
Zhen Liu ◽  
Shenmeng Gao ◽  
Li Zhou ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cell Lines ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Myelogenous Leukemia ◽  
Great Success

Abstract Despite of the great success of tyrosine kinase inhibitor in the therapy of chronic myelogenous leukemia (CML), CML is still not curable. Further investigation on the molecular mechanism of CML pathogenesis and identification of novel therapeutic target are required. In this study, we found that overexpression of CML characterized Bcr/Abl oncoprotein could significantly upregulate the expression of ubiquitin-specific protease Usp47. Also, increased expression of Usp47 was observed in primary CML cells and its expression was associated with the treatment response of imatinib, the first generation of tyrosine kinase inhibitor. Furthermore, Usp47 knockdown could inhibit the proliferation of K562 cells in vitro and in vivo. P22077, a Usp47 inhibitor, could inhibit the proliferation of CML cell lines, which comprise BCR/ABL mutation, including the T315I mutation. P22077 inhibits the proliferation of primary CML cells sensitive or resistant to imatinib. The colony forming activity of CD34+ from CML primary cells but not from normal cord blood cells were also inhibited by P22077. We further demonstrated that inactivation of STAT5 significantly reduce the expression of Usp47, indicating that BCR/ABL-induced upregulation of Usp47 is mediated by STAT5 activition. Interestingly, Usp47 could interact with Sirt1, another STAT5 target gene. Inactivation of Usp47 reduces the expression of Sirt1 in CML cell lines and primary CML cells. Taken together, we demonstrated that Usp47 plays an critical role in CML, revealing a novel BCR/ABL/STAT5/Usp47/Sirt1 signaling pathway in CML, providing a potential target to overcome tyrosine kinase inhibitor resistance. Disclosures No relevant conflicts of interest to declare.

Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl–positive cells

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3195-3199 ◽  
Author(s):  
J. Tyler Thiesing ◽  
Sayuri Ohno-Jones ◽  
Kathryn S. Kolibaba ◽  
Brian J. Druker
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Abl Tyrosine Kinase ◽  
Abl Tyrosine Kinase Inhibitor

Abstract Chronic myelogenous leukemia (CML), a malignancy of a hematopoietic stem cell, is caused by the Bcr-Abl tyrosine kinase. STI571(formerly CGP 57148B), an Abl tyrosine kinase inhibitor, has specific in vitro antileukemic activity against Bcr-Abl–positive cells and is currently in Phase II clinical trials. As it is likely that resistance to a single agent would be observed, combinations of STI571 with other antileukemic agents have been evaluated for activity against Bcr-Abl–positive cell lines and in colony-forming assays in vitro. The specific antileukemic agents tested included several agents currently used for the treatment of CML: interferon-alpha (IFN), hydroxyurea (HU), daunorubicin (DNR), and cytosine arabinoside (Ara-C). In proliferation assays that use Bcr-Abl–expressing cells lines, the combination of STI571 with IFN, DNR, and Ara-C showed additive or synergistic effects, whereas the combination of STI571 and HU demonstrated antagonistic effects. However, in colony-forming assays that use CML patient samples, all combinations showed increased antiproliferative effects as compared with STI571 alone. These data indicate that combinations of STI571 with IFN, DNR, or Ara-C may be more useful than STI571 alone in the treatment of CML and suggest consideration of clinical trials of these combinations.

scholarly journals Multi-unit ribozyme-mediated cleavage of bcr-abl mRNA in myeloid leukemias

Blood ◽  
1995 ◽  
Vol 85 (8) ◽  
pp. 2162-2170 ◽  
Author(s):  
LH Leopold ◽  
SK Shore ◽  
TA Newkirk ◽  
RM Reddy ◽  
EP Reddy
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Fusion Gene ◽  
Folate Receptor ◽  
Philadelphia Chromosome ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Myeloid Leukemias ◽  
Transforming Activity ◽  
Cleavage Reactions

Chronic myelogenous leukemia is characterized by the Philadelphia chromosome, which at the molecular level results from the fusion of the bcr gene on chromosome 22 and the abl gene on chromosome 9. The bcr-abl fusion gene encodes a novel tyrosine kinase with transforming activity. In this study, we have synthesized a multi-unti ribozyme that targets bcr-abl mRNA. In vitro ribozyme cleavage reactions show increased cleavage efficiency of this multi-unit ribozyme compared with single or double ribozymes. The multiunit ribozyme was then transfected into murine myeloblasts transformed with the bcr-abl gene (32D cells). Ribozyme transfection was accomplished either by liposomes or using follic acid-polylysine as a carrier. Multi-unit ribozyme transfection reduced the level of bcr-abl mRNA 3 logs when transfected via folate receptor-mediated uptake into transformed 32D cells. These results suggest that a multi-unit ribozyme could be an effective therapeutic agent for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia.

Sign in / Sign up

Export Citation Format

Share Document