Philadelphia chromosome positive chronic myeloid leukemia with 5q deletion at diagnosis

Haidary, Ahmed Maseh; Ahmed, Zeeshan; Abdul‐Ghafar, Jamshid; Rahmani, Soma; Noor, Sarah; Erfani, Farahnaz; Ahmad, Maryam; Lakanwall, Naeem; Malakzai, Haider Ali; Ibrahimkhil, Abdul Sami; Esmat, Esmatullah; Haidari, Mujtaba; Yousufzai, Nimattullah; Sharif, Samuel; Saqib, Abdul Hadi

doi:10.1186/s13039-021-00539-0

Cited by 5 publications

(3 citation statements)

References 26 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the case of children (CML), it makes up 15% of all instances of myeloid leukemia. Its prevalence rises with age, reaching 1.2 instances per million annually in teenagers [ 2 ]. The Philadelphia chromosome (Ph) is what distinguishes CML from other myeloproliferative neoplasms; however, albeit rarely, the Ph+ may also be seen in MPN other than CML [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Artificial Intelligence Assisted Pharmacophore Design for Philadelphia Chromosome-Positive Leukemia with Gamma-Tocotrienol: A Toxicity Comparison Approach with Asciminib

et al. 2023

View full text Add to dashboard Cite

BCR-ABL1 is a fusion protein as a result of a unique chromosomal translocation (producing the so-called Philadelphia chromosome) that serves as a clinical biomarker primarily for chronic myeloid leukemia (CML); the Philadelphia chromosome also occurs, albeit rather rarely, in other types of leukemia. This fusion protein has proven itself to be a promising therapeutic target. Exploiting the natural vitamin E molecule gamma-tocotrienol as a BCR-ABL1 inhibitor with deep learning artificial intelligence (AI) drug design, this study aims to overcome the present toxicity that embodies the currently provided medications for (Ph+) leukemia, especially asciminib. Gamma-tocotrienol was employed in an AI server for drug design to construct three effective de novo drug compounds for the BCR-ABL1 fusion protein. The AIGT’s (Artificial Intelligence Gamma-Tocotrienol) drug-likeliness analysis among the three led to its nomination as a target possibility. The toxicity assessment research comparing AIGT and asciminib demonstrates that AIGT, in addition to being more effective nonetheless, is also hepatoprotective. While almost all CML patients can achieve remission with tyrosine kinase inhibitors (such as asciminib), they are not cured in the strict sense. Hence it is important to develop new avenues to treat CML. We present in this study new formulations of AIGT. The docking of the AIGT with BCR-ABL1 exhibited a binding affinity of −7.486 kcal/mol, highlighting the AIGT’s feasibility as a pharmaceutical option. Since current medical care only exclusively cures a small number of patients of CML with utter toxicity as a pressing consequence, a new possibility to tackle adverse instances is therefore presented in this study by new formulations of natural compounds of vitamin E, gamma-tocotrienol, thoroughly designed by AI. Even though AI-designed AIGT is effective and adequately safe as computed, in vivo testing is mandatory for the verification of the in vitro results.

show abstract

Section: Introductionmentioning

confidence: 99%

Artificial Intelligence Assisted Pharmacophore Design for Philadelphia Chromosome-Positive Leukemia with Gamma-Tocotrienol: A Toxicity Comparison Approach with Asciminib

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the accumulation of myeloid cells in the blood ( Ning et al, 2020 ). CML is highly associated with chromosomal translocations, as the translocation between chromosomes 9 and 22 t (9; 22) (q34; q11), known as Philadelphia chromosome (Ph+), which is found in 95% of diagnosed cases ( Haidary et al, 2021 ). The Ph + encodes for chimeric protein BCR-ABL1, which is a constitutively active tyrosine kinase (TK) linked to cellular growth, survival, and cell differentiation in CML ( Amarante-Mendes et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action

et al. 2022

View full text Add to dashboard Cite

Chronic myeloid leukemia (CML) is caused by constitutively active fusion protein BCR-ABL1, and targeting ABL1 is a promising therapy option. Imatinib, dasatinib, and nilotinib have all been shown to work effectively in clinical trials. ABL1 mutations, particularly the T315I gate-keeper mutation, cause resistance in patients. As a result, broad-spectrum ABL1 medicines are desperately needed. In order to screen potential drugs targeting CML, mebendazole (MBZ) was subjected to the in vitro test against CML cell lines (K562 and FEPS) and computational assays. The antiproliferative effect of MBZ and the combination with tyrosine kinase inhibitors (TKIs) was tested using end-point viability assays, cell cycle distribution analysis, cell membrane, and mitochondrial dyes. By interrupting the cell cycle and causing cell death, MBZ and its combination with imatinib and dasatinib have a significant antiproliferative effect. We identified MBZ as a promising “new use” drug targeting wild-type and mutant ABL1 using molecular docking. Meanwhile, we determined which residues in the allosteric site are important in ABL1 drug development. These findings may not only serve as a model for repositioning current authorized medications but may also provide ABL1-targeted anti-CML treatments a fresh lease of life.

show abstract

“…Over the past half century, there has been significant advances in the field of molecular biology that has led to better understanding of the pathophysiology of leukemias, including acute lymphoblastic leukemia [ 2 ]. Where in 1970s, the diagnosis of acute leukemias was based on clinical and morphological features of the blast cells, in today's era, the molecular‐cytogenetic modalities are used not only for diagnostic purposes but also for disease prognostication [ 3 , 4 ]. Next‐generation sequencing and epigenetic studies are now being utilized to identify the molecular markers that can be targeted during therapy [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Acute lymphoblastic leukemia with clonal evolution due to delay in chemotherapy: A report of a case

Haidary

Saadaat

Abdul‐Ghafar

et al. 2022

eJHaem

Self Cite

View full text Add to dashboard Cite

Clonal evolution in acute leukemias is one of the most important factors that leads to therapeutic failure and disease relapse. Delay in therapeutic intervention is one of the reasons that leads toward clonal evolution. In this report, we present a case of acute lymphoblastic leukemia in which therapeutic delay resulted in clonal evolution that was detected by conventional karyotyping and was responsible for non-responsiveness of the disease to conventional chemotherapy. A 17-year-old boy presented with generalized body aches, rapidly progressive pallor and lethargy. Bone marrow analysis was consistent with the diagnosis of B-cell ALL. Karyotypic analysis revealed 46, XY male karyotype. The patient left the hospital due to financial reasons and after 40 days came back to the hospital. Repeated bone marrow analysis including cytogenetic studies revealed presence of three different clones of blast cells: one clone showed 46, XY with del(9p) and t (11;14), second clone showed 46, XY with del(7q) and del(9p), and the third clone showed 46, XY normal karyotype. The patient did not respond to chemotherapy and died within 1 week of induction chemotherapy (HyperCVAD-A). Timely diagnosis and institution of chemotherapy in acute leukemias patients is the key to prevent clonal evolution and thus resistance of the disease to therapeutic interventions.

show abstract

Philadelphia chromosome positive chronic myeloid leukemia with 5q deletion at diagnosis

Cited by 5 publications

References 26 publications

Artificial Intelligence Assisted Pharmacophore Design for Philadelphia Chromosome-Positive Leukemia with Gamma-Tocotrienol: A Toxicity Comparison Approach with Asciminib

Artificial Intelligence Assisted Pharmacophore Design for Philadelphia Chromosome-Positive Leukemia with Gamma-Tocotrienol: A Toxicity Comparison Approach with Asciminib

Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action

Acute lymphoblastic leukemia with clonal evolution due to delay in chemotherapy: A report of a case

Contact Info

Product

Resources

About