Novel ABL1 mutation in a Moroccan CML patient with Imatinib resistance.

Tyrosine Kinase Inhibitors (TKI), such as Imatinib, are known for their effectiveness in achieving complete remission from Chronic Myeloid Leukemia (CML), a malignancy caused by a reciprocal translocation between the terminal fragments of the long arms of chromosomes 9 and 22 that leads to the famous chimeric BCR::ABL1 gene. Mutations in this fusion gene may induce resistance to TKI treatment, which requires prescribing a second-, or third-generation TKI medication. We report here a case of a Moroccan CML patient with secondary resistance to the frontline TKI treatment (Imatinib), in which, BCR::ABL1 cDNA sequencing reveals the novel mutation p.K375M at the ABL1 Kinase Domain. In-silico prediction tools confirm the pathogenicity of the p.K375M substitution. Homology analysis indicated that the residue is highly conserved and located in a stable region. This potentially pathogenic mutation is likely to disrupt the BCR::ABL1-Imatinib binding, leading to the observed resistance. To overcome the treatment resistance, Imatinib should be substituted with a second-generation TKI medication, such as Dasatinib, Bosutinib, or Nilotinib. The present study further widens the spectrum of TKI resistance mutations and emphasizes particularly the crucial role of molecular investigation in personalizing treatment for CML patients, ensuring efficient follow-up and appropriate healthcare.

El Bouchikhi I ，Azami Idrissi H ，Lazraq A ，El Makhzen B ，Ahakoud M ，Berrady R ，Ouldim K ，Bouguenouch L ，El-Azami-El-Idrissi M ... -  《Cancer Genetics》

Computer-aided design of imatinib derivatives: Overcoming drug-resistance in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a hematologic condition characterized by the overexpression of stem blood cells in the bone marrow. The Philadelphia chromosome encodes the oncogenic tyrosine kinase BCR-ABL, which is a hallmark of CML. Imatinib, a phenylamino pyrimidine derivative, was the first tyrosine kinase inhibitor (TKI) approved in 2001 for CML. Despite launching a new era in cancer targeted therapy, acquired resistance occurred due to the point mutation of a gatekeeper residue (Thr315Ile) at the BCR-ABL catalytic pocket. There are no approved medications for Thr315Ile-BCR-ABL harboring CML patients. Present study was aimed at the in silico identification of synthetically accessible imatinib derivatives that are likely to bind a frequent Thr315Ile-BCR-ABL and overcome drug resistance. 4-((4-benzylpiperazin-1-yl) methyl)-N-(4-methyl-3-(4-(pyridine-3-yl) pyrimidine-2-amino) phenyl) benzamide (SCHEMBL12127861) and 4-(methoxy (methyl) amino)-N-(3-methyl-5-(pyrido[3,4-b] pyrazin-2-yl thio) phenyl) benzamide (18) were revealed as top-binders. Molecular dynamics simulations and free energy calculations conferred stable binding features Thr315Ile-BCR-ABL. A new binding model was suggested for 18 that resided outside the kinase domain (∼15 Å from Ile315). Considering stability and binding energy compared to imatinib, the intended binding model may be the subject of further evaluations to overwhelm drug resistance. SCHEMBL12127861 had appropriate and more buried accommodation than imatinib near the DFG motif and P-loop of the kinase domain. Hydrogen bonds, π-cation interaction, salt bridge, and a vdW cooperative contacts mediated the complex stability. Although validation of proposed models is to be achieved, this study identified synthetically accessible in silico hits with tight binding to the clinically frequent mutant BCR-ABL phenotypes in Thr315Ile-positive CML patients.

Gholizadeh S ，Panahi N ，Razzaghi-Asl N 《-》

Occurrence of Existing BCR-ABL Baseline Mutations and Associated Haplotype (NmR) Among CML Patients with Diverse IM Response: A Hospital-based Study from North-East India.

Highly polymorphic BCR-ABL kinase domains have been reported to harbor more than a hundred mutations, and among these, 40-60% have been identified as influencers of imatinib mesylate (IM) resistance. The emergence of IM resistance poses a significant challenge in the management of Chronic Myeloid Leukemia (CML). M351T (rs121913457), E255K (rs387906517), and Y253H (rs121913461) are of particular clinical significance due to their association with high-level imatinib resistance. This study was conducted to investigate the potential role of three significant SNPs in CML progression due to IM resistance. During the study period from 2018 to 2022 (48 months), the blood samples from 219 Reverse transcriptase-PCR-confirmed CML patients following RNA extraction and cDNA preparation were subjected to M351T, E255K, and Y253H mutation analysis by PCR-RFLP. After agarose gel visualization, the samples were subjected to Sanger sequencing to confirm the nucleotide change at the polymorphic loci. The wild-type genotype of all three ABL1 SNPs under investigation exhibits a significant reduction in frequency among IM non-responders compared to the responder group. The CGT haplotype frequency exhibits a significant difference between IM responder (4.2%) and non-responder (11.8%) (p = 0.002 < 0.05). Further, CGC haplotype was observed solely among the imatinib non-responder patients with a frequency percentage of 3.3% (p = 0.004), whereas the said genotype was absent among the responder group. A reduced overall survival rate was observed with deviation from wild-type genotype (M351T loci (T > C) with 1.217 times, E255K (G > A) with 1.485 and Y253H (T > C) with 1.399 times increase in hazard ratio) thereby enhancing mortality risk due to disease progression. The significant increase in the frequency of M351T, E255K, and Y253H loci among the IM non-responder group indicated their probable association with the development of IM resistance among CML patients. A haplotype frequency distribution pattern analysis of ABL1 loci further identified the CGC haplotype as an independent predictor for IM resistance. As such the study highlights the importance of patient characteristics, genotype distribution, and haplotype frequency distribution in predicting the response to IM treatment and clinical outcomes of CML patients.

Hazarika G ，Kalita MJ ，Das PP ，Kalita S ，Dutta K ，Lahkar L ，Rajkonwar A ，Idris MG ，Khamo V ，Kusre G ，Medhi S ... -  《-》

Chronic Myeloid Leukemia: A Review.

Jabbour E ，Kantarjian H 《-》

Next-generation deep sequencing improves detection of BCR-ABL1 kinase domain mutations emerging under tyrosine kinase inhibitor treatment of chronic myeloid leukemia patients in chronic phase.

Machova Polakova K ，Kulvait V ，Benesova A ，Linhartova J ，Klamova H ，Jaruskova M ，de Benedittis C ，Haferlach T ，Baccarani M ，Martinelli G ，Stopka T ，Ernst T ，Hochhaus A ，Kohlmann A ，Soverini S ... -  《-》