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The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Philadelphia chromosome (Ph) and is a hallmark of chronic myeloid leukemia (CML). In leukemia cells, Ph not only impairs the physiological signaling pathways but also disrupts genomic stability. This aberrant fusion gene encodes the breakpoint cluster region‐proto‐oncogene tyrosine‐protein kinase (BCR‐ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity. The kinase activity is responsible for maintaining proliferation, inhibiting differentiation, and conferring resistance to cell death. During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase, the expression patterns of different BCR‐ABL1 transcripts vary. Each BCR‐ABL1 transcript is present in a distinct leukemia phenotype, which predicts both response to therapy and clinical outcome. Besides CML, the Ph is found in acute lymphoblastic leukemia, acute myeloid leukemia, and mixed‐phenotype acute leukemia. Here, we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph‐positive leukemia and highlight key findings regarding leukemogenesis.

Background The Philadelphia chromosome (Ph) represented a finding of chronic myeloid leukemia (CML) in most cases which formed from t (9; 22) (q34; q11) resulting in the Breakpoint cluster region‐Abelson tyrosine‐protein kinase1 (BCR‐ABL1) fusion gene. Assuming CCE's inaccuracies in diagnosing CML and FISH's limitations with low BCR‐ABL1 percentages, a Predicted‐FISH (Pred‐FISH) was developed. This model predicts treatment response during follow‐up by integrating qRT‐PCR results, White Blood Cell (WBC) counts, and Cytogenetic Response data. Methods Quantitative Real‐Time Polymerase Chain Reaction Analysis (qRT‐PCR), fluorescence in situ hybridization (FISH), and Conventional Cytogenetic Examination (CCE or Karyotyping) have been used in the detection and follow‐up of CML patients. The study included 110 individuals, divided into three groups: 31.82% (35 individuals) were newly diagnosed CML patients, another 22.73% (25 individuals) were healthy control samples, and the remaining 45.45% (50 individuals) were previously diagnosed CML patients. Results Include BCR‐ABL1 fusion gene levels detected by qRT‐PCR, Ph chromosome presence t (9; 22) (q34; q11) observed by CCE, and WBC counts. The FISH test, used to confirm disease in new patients before treatment, was compared to CCE results due to its insensitivity in certain conditions. Data from CCE, FISH, qRT‐PCR, and WBC for newly diagnosed patients provided a standard for evaluating the Predicted‐FISH. Conclusion The FISH technique excels in disease detection with over 98% accuracy and high sensitivity. QRT‐PCR is effective for monitoring CML and BCR‐ABL1 gene levels, indicating MMR and DMR. CCE, while useful for posttreatment monitoring, is less accurate in measuring treatment response over time. Fusion Metrix for The FISH Model vs CCE for 50 Patients for three Periods.

The constitutively active BCR-ABL1 tyrosine kinase, found in t(9;22)(q34;q11) chromosomal translocation-derived leukemia, initiates an extremely complex signaling transduction cascade that induces a strong state of resistance to chemotherapy. Targeted therapies based on tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, have revolutionized the treatment of BCR-ABL1-driven leukemia, particularly chronic myeloid leukemia (CML). However, TKIs do not cure CML patients, as some develop TKI resistance and the majority relapse upon withdrawal from treatment. Importantly, although BCR-ABL1 tyrosine kinase is necessary to initiate and establish the malignant phenotype of Ph-related leukemia, in the later advanced phase of the disease, BCR-ABL1-independent mechanisms are also in place. Here, we present an overview of the signaling pathways initiated by BCR-ABL1 and discuss the major challenges regarding immunologic/pharmacologic combined therapies.

Cancer is driven by genomic lesions and malignancy‐promoting transcriptional programs. In blood cancers, both are often interconnected as lesions frequently affect transcription factor (TF)‐encoding genes. TFs largely function through enhancers, and enhancer deregulation is linked to cancer initiation and progression. Consequently, enhancer‐targeting drugs are in trials for several advanced hematologic cancers. However, for cancers not driven by TF‐related lesions, it is less clear how their transcriptional programs are established; if oncogenesis involves enhancer‐deregulation, and if they are sensitive to therapeutic enhancer‐targeting. Here, we explore this for Philadelphia chromosome‐positive (Ph+) B‐lineage leukemia (B‐ALL), the most common B‐ALL in adults with a historically poor prognosis. Ph+B‐ALL is driven by BCR::ABL1, a kinase without TF‐related function. We report that malignant transformation and transcriptional reprogramming by BCR::ABL1 is indeed defined by enhancer reprogramming and that enhancer signatures differentiate Ph+B‐ALL from other leukemias. Mechanistically, we show that BCR::ABL1 itself induces enhancer activation, through its kinase activity and via kinase‐dependent activation of STAT5, ETV5, and MYC. Consequently, BCR::ABL1‐induced genes are hypersensitive to enhancer inhibition, and Ph+B‐ALL cells are hypersensitive to enhancer‐targeting drugs. Enhancer‐targeting further improves the efficacy of BCR::ABL1 kinase inhibitors used for Ph+B‐ALL therapy, especially in cells from IKZF1 PLUS patients that most frequently relapse from current treatment, suggesting enhancer‐targeting as a potential promising addition to current therapy.

BCR‐ABL1 gene fusion associated with additional DNA lesions involves the pathogenesis of chronic myelogenous leukemia (CML) from a chronic phase (CP) to a blast crisis of B lymphoid (CML‐LBC) lineage and BCR‐ABL1+ acute lymphoblastic leukemia (BCR‐ABL1+ ALL). The recombination‐activating gene RAG1 and RAG2 (collectively, RAG) proteins that assemble a diverse set of antigen receptor genes during lymphocyte development are abnormally expressed in CML‐LBC and BCR‐ABL1+ ALL. However, the direct involvement of dysregulated RAG in disease progression remains unclear. Here, we generate human wild‐type (WT) RAG and catalytically inactive RAG‐expressing BCR‐ABL1+ and BCR‐ABL1− cell lines, respectively, and demonstrate that BCR‐ABL1 specifically collaborates with RAG recombinase to promote cell survival in vitro and in xenograft mice models. WT RAG‐expressing BCR‐ABL1+ cell lines and primary CD34+ bone marrow cells from CML‐LBC samples maintain more double‐strand breaks (DSB) compared to catalytically inactive RAG‐expressing BCR‐ABL1+ cell lines and RAG‐deficient CML‐CP samples, which are measured by γ‐H2AX. WT RAG‐expressing BCR‐ABL1+ cells are biased to repair RAG‐mediated DSB by the alternative non–homologous end joining pathway (a‐NHEJ), which could contribute genomic instability through increasing the expression of a‐NHEJ‐related MRE11 and RAD50 proteins. As a result, RAG‐expressing BCR‐ABL1+ cells decrease sensitivity to tyrosine kinase inhibitors (TKI) by activating BCR‐ABL1 signaling but independent of the levels of BCR‐ABL1 expression and mutations in the BCR‐ABL1 tyrosine kinase domain. These findings identify a surprising and novel role of RAG in the functional specialization of disease progression in BCR‐ABL1+ leukemia through its endonuclease activity. BCR‐ABL1 associates with RAG to promote BCR‐ABL1+ cell survival in vitro and in vivo. The endonuclease activity of RAG drives BCR‐ABL1+ cells to choose the a‐NHEJ pathway in response to DNA damage. RAG stimulates BCR‐ABL1 signaling to reduce TKI therapeutic efficacy, albeit independently of BCR‐ABL1 expression and mutations in the BCR‐ABL1 kinase domain.

Hydroxyurea (HU) cytoreduction is usually administered to patients with chronic myeloid leukemia before starting any tyrosine kinase inhibitors (TKIs) therapy. However, up to date, there is no evidence of any benefit of hydroxyurea pre-treatment. Conversely, evidence has been provided on both the prognostic significance of the quantitative assessment of BCR::ABL1 expression at diagnosis and the individual decline of the BCR::ABL1 slope. In this view, we assumed that any kind of treatment administered before a confirmed diagnosis of chronic myeloid leukemia might change the amount of BCR::ABL1 transcript levels. To this purpose, we evaluated leukocyte counts and BCR::ABL1 quantitative expression either at diagnosis (baseline and no therapy) and on day 7 and day 14 of treatment in a cohort of 45 unselected patients with newly diagnosed chronic myeloid leukemia in the chronic phase. After informed consent, 21 of them received HU cytoreduction for 14 days before starting TKI treatment (HU group), whereas the other 24 patients received frontline TKI therapy without HU pre-treatment (TKI group). Our findings showed that: (i) there is no benefit from HU cytoreduction in patients affected with chronic myeloid leukemia before starting treatment with TKIs; (ii) any kind of therapy administered before a confirmed diagnosis of chronic myeloid leukemia might change the amount of BCR::ABL1 expression levels.

In precursor B-cell lineage acute lymphoblastic leukemia (BCP-ALL), leukemic cells harbor genetic abnormalities that play an important role in the diagnosis, prognosis, and treatment. A subgroup of BCP-ALL is characterized by the presence of a Philadelphia (Ph) chromosome and a chimeric BCR::ABL1 gene, whereas in another subgroup, leukemic cells exhibit near-haploidy with chromosome number 24-30. This study presents the third documented case of BCP-ALL in which a near haploid clone concurrently displayed a Ph chromosome/BCR::ABL1. Bone marrow cells obtained at diagnosis from a 25-year-old man with BCP-ALL were genetically investigated using G-banding, fluorescence in situ hybridization, and array comparative genomic hybridization. Leukemic cells had an abnormal karyotype 28,X,-Y,+6,+10,+18,+21,+ der(22) t(9;22)(q34;q11)[13]/28,idem, del(10)(q24),der(12) t(1;12) (q21;p13)[2]/46,XY[3], retained heterozygosity of the disomic chromosomes 6, 10, 18, and 21, had breakpoints in introns 1 of ABL1 and BCR, and carried a BCR::ABL1 chimera encoding the 190 kDa BCR::ABL1 protein. The coexistence of the BCR::ABL1 chimera and near-haploidy in the same cytogenetic clone suggested a possible synergistic role in leukemogenesis, with the former activating signaling pathways and the latter disrupting gene dosage balance.

Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that originates from a translocation event between chromosome 9 and chromosome 22 within the hematopoietic stem cell compartment. The resultant fusion protein BCR::ABL1 is a constitutively active tyrosine kinase that can phosphorylate multiple downstream signaling molecules to promote cellular survival and inhibit apoptosis. Currently, tyrosine kinase inhibitors (TKIs), which impair ABL1 kinase activity by preventing ATP entry, are widely used as a successful therapeutic in CML treatment. However, disease relapses and the emergence of resistant clones have become a critical issue for CML therapeutics. Two main reasons behind the persisting obstacles to treatment are the acquired mutations in the ABL1 kinase domain and the presence of quiescent CML leukemia stem cells (LSCs) in the bone marrow, both of which can confer resistance to TKI therapy. In this article, we systemically review the structural and molecular properties of the critical domains of BCR::ABL1 and how understanding the essential role of BCR::ABL1 kinase activity has provided a solid foundation for the successful development of molecularly targeted therapy in CML. Comparison of responses and resistance to multiple BCR::ABL1 TKIs in clinical studies and current combination treatment strategies are also extensively discussed in this article.

Small‐molecule‐induced degradation of mutant Bcr‐Abl1 provides a potential approach to overcome Bcr‐Abl1 tyrosine kinase inhibitor (TKI)‐resistant chronic myeloid leukemia (CML). Our previous study reported that a synthetic steroidal glycoside SBF‐1 showed remarkable anti‐CML activity by inducing the degradation of native Bcr‐Abl1 protein. Here, we observed the comparable growth inhibition for SBF‐1 in CML cells harboring T315I mutant Bcr‐Abl1 in vitro and in vivo. SBF‐1 triggered its degradation through disrupting the interaction between protein‐tyrosine phosphatase 1B (PTP1B) and Bcr‐Abl1. Using SBF‐1 as a tool, we found that Tyr46 in the PTP1B catalytic domain and Tyr852 in the Bcr‐Abl1 pleckstrin‐homology (PH) domain are critical for their interaction. Moreover, the phosphorylation of Tyr1086 within the Bcr‐Abl1 SH2 domain recruited the E3 ubiquitin ligase c‐Cbl to catalyze K27‐linked ubiquitin chains, which serve as a recognition signal for p62‐dependent autophagic degradation. PTP1B dephosphorylated Bcr‐Abl1 at Tyr1086 and prevented the recruitment of c‐Cbl, leading to the stability of Bcr‐Abl1. This study unravels the action mechanism of PTP1B in stabilizing Bcr‐Abl1 protein and indicates that the PTP1B‐Bcr‐Abl1 interaction might be one of druggable targets for TKI‐resistant CML with point mutations. A synthetic steroidal glycoside SBF‐1 could trigger the degradation of T315I mutant Bcr‐Abl1 protein via disrupting the interaction between PTP1B and Bcr‐Abl1, and overcome TKI‐resistant CML. Using SBF‐1 as a tool, we identified the amino acids crucial for the interaction and unraveled the action mechanism of PTP1B in stabilizing Bcr‐Abl1 protein.