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BCR (gene)
BCR (gene)
BCR (gene)
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BCR
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesBCR, Bcr, 5133400C09Rik, AI561783, AI853148, mKIAA3017, ALL, BCR1, CML, D22S11, D22S662, PHL, RhoGEF and GTPase activating protein, BCR gene, BCR activator of RhoGEF and GTPase
External IDsOMIM: 151410; MGI: 88141; HomoloGene: 3192; GeneCards: BCR; OMA:BCR - orthologs
Orthologs
SpeciesHumanMouse
Entrez

613

110279

Ensembl

ENSG00000186716

ENSMUSG00000009681

UniProt

P11274

Q6PAJ1

RefSeq (mRNA)

NM_004327
NM_021574

NM_001081412

RefSeq (protein)

NP_004318
NP_067585

NP_001074881

Location (UCSC)Chr 22: 23.18 – 23.32 MbChr 10: 74.9 – 75.02 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Bcr-Abl oncoprotein oligomerisation domain
structure of the bcr-abl oncoprotein oligomerization domain
Identifiers
SymbolBcr-Abl_Oligo
PfamPF09036
InterProIPR015123
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

The breakpoint cluster region protein (BCR) also known as renal carcinoma antigen NY-REN-26 is a protein that in humans is encoded by the BCR gene. BCR is one of the two genes in the BCR-ABL fusion protein, which is associated with the Philadelphia chromosome. Two transcript variants encoding different isoforms have been found for this gene.

Structure

[edit]
Schematic of the BCR-ABL formation through chromosomal translocation

The BCR-ABL oncoprotein oligomerisation domain found at the N-terminus of BCR is essential for the oncogenicity of the BCR-ABL fusion protein. The BCR-ABL oncoprotein oligomerisation domain consists of a short N-terminal helix (alpha-1), a flexible loop and a long C-terminal helix (alpha-2). Together these form an N-shaped structure, with the loop allowing the two helices to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel coiled coil between the alpha-2 helices and domain swapping of two alpha-1 helices, where one alpha-1 helix swings back and packs against the alpha-2 helix from the second monomer. Two dimers then associate into a tetramer.[5] Structure-based engineering starting from the antiparallel coiled coil domain of the BCR-ABL oncoprotein (BCR30-65) resulted in a new pH-sensitive homodimeric antiparallel coiled coil.[6]

Function

[edit]

Although the BCR-ABL fusion protein has been much studied, the function of the normal BCR gene product is still not clear. The protein has serine/threonine kinase activity and is a guanine nucleotide exchange factor for the Rho family of GTPases including RhoA.[7][8]

Interactions

[edit]

The BCR protein has been shown to interact with:

Clinical significance

[edit]

A reciprocal translocation between chromosomes 22 and 9 produces the Philadelphia chromosome, which is often found in patients with chronic myelogenous leukemia. The chromosome 22 breakpoint for this translocation is located within the BCR gene. The translocation produces a fusion protein that is encoded by sequence from both BCR and ABL, the gene at the chromosome 9 breakpoint.[30]

See also

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References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

BCR (gene)

View on Grokipedia
from Grokipedia
The BCR gene (Breakpoint Cluster Region), also known as BCR activator of RhoGEF and , encodes a protein that functions as a GTPase-activating protein (GAP) for Rho family , such as Rac1 and Cdc42, thereby regulating actin cytoskeleton dynamics, , and pathways involved in cellular proliferation and differentiation. Located on the long arm of at position 22q11.23, the gene spans approximately 130 kilobases and consists of 23 exons, producing multiple transcript variants that result in a cytoplasmic protein with domains for oligomerization, SH2 binding, GTP/GDP exchange, and GTPase activation. In normal physiology, the BCR protein is ubiquitously expressed across human tissues, with particularly high levels in the brain and testis, where it modulates superoxide production, inhibits certain oncogenic transformations, and participates in pathways like RAS, PI-3K/Akt, and JAK/STAT signaling. However, the gene's most prominent role is in oncogenesis, as it serves as a fusion partner in the t(9;22)(q34;q11) reciprocal translocation that generates the Philadelphia chromosome, producing the oncogenic BCR-ABL1 fusion protein (e.g., p210 in chronic myeloid leukemia or p190 in acute lymphoblastic leukemia). This fusion constitutively activates tyrosine kinase activity, leading to uncontrolled cell growth, genomic instability, and resistance to apoptosis, which underlies approximately 95% of chronic myeloid leukemia cases, 25-30% of adult B-cell acute lymphoblastic leukemia, and rare instances of acute myeloid leukemia. The BCR-ABL1 oncoprotein is a primary target for tyrosine kinase inhibitors like imatinib, revolutionizing treatment for these hematologic malignancies.

Genomic and Molecular Features

Gene Location and Organization

The BCR gene is located on the long arm of human chromosome 22 at cytogenetic band 22q11.23 (GRCh38: 23,180,509–23,318,037). It spans approximately 138 kb of genomic DNA, encompassing 23 exons that encode the full-length protein. The promoter region of the BCR gene includes a CpG island upstream of the primary transcription start site, which serves as a key regulatory element for transcriptional initiation. This CpG island is rich in unmethylated cytosine-guanine dinucleotides and is associated with housekeeping gene-like expression patterns, though it can undergo methylation changes that modulate BCR expression levels. Additional regulatory elements, such as potential transcription factor binding sites, are present in the 5' flanking region to fine-tune gene activity in response to cellular signals. The BCR gene demonstrates strong evolutionary conservation across mammals, reflecting its essential roles in cellular signaling. Orthologs are present in species such as (Bcr gene on 10), rat, and other vertebrates, with and protein sequences showing high similarity that preserves functional domains. For instance, the and orthologs exhibit substantial sequence conservation, enabling comparative studies in model organisms. Within the BCR gene, specific genomic breakpoints define regions prone to recombination, notably the major breakpoint cluster region (m-bcr), a 5.8 kb segment located between exons 14 and 15. This cluster is a hotspot for the t(9;22)(q34;q11) translocation that generates the BCR-ABL fusion gene in chronic myeloid leukemia.

Transcript Variants and Isoforms

The BCR gene undergoes alternative splicing to generate multiple transcript variants, with two primary protein-coding isoforms documented in reference databases. The longer transcript variant (NM_004327.4, approximately 7 kb) encodes the full-length p160 BCR isoform, comprising 1271 amino acids and characterized by an N-terminal serine/threonine kinase domain, a Dbl homology domain acting as a guanine nucleotide exchange factor (GEF), a pleckstrin homology (PH) domain, and a C-terminal GTPase-activating protein (GAP) domain for Rho family GTPases. A shorter transcript variant (NM_021574.3, approximately 6.6 kb) arises from the exclusion of a single in-frame exon, resulting in the p130 BCR isoform of 1227 amino acids that retains the core functional domains but exhibits subtle structural differences potentially affecting oligomerization or interactions. These isoforms share the same N- and C-termini, preserving overall domain architecture while allowing for functional diversification. Expression of BCR transcripts is ubiquitous across tissues but shows variation, with elevated levels in hematopoietic cells, , and testis, as evidenced by sequencing data from multiple tissues (e.g., RPKM values up to 14.9 in testis). This tissue-specific pattern likely contributes to BCR's roles in and cytoskeletal dynamics in proliferative or motile cell types. Variations in the untranslated regions (UTRs) further modulate expression: the 5' UTR (spanning ~450 nucleotides in both variants) is highly GC-rich (~80%), featuring a , , and predicted secondary structures that impede ribosomal scanning and reduce translation efficiency under basal conditions. The 3' UTR (~2.5 kb) contains canonical signals and sites, influencing mRNA stability through potential binding of regulatory microRNAs or RNA-binding proteins. These UTR elements enable fine-tuned post-transcriptional control, adapting BCR expression to cellular demands. The p160 and p130 isoforms exhibit distinct subcellular distributions and functional nuances, with p160 predominantly localizing to the where it facilitates regulation and remodeling, while p130 shows partial nuclear accumulation potentially linking it to transcriptional modulation. Both isoforms display serine/ activity capable of autophosphorylation and substrate , as well as GAP activity toward Rac , but the shorter p130 may exhibit reduced potency due to conformational changes from , leading to isoform-specific interactions in signaling cascades. Ensembl predicts additional alternative splice forms producing truncated proteins (e.g., 1227 or fewer ), some potentially lacking partial domains and resulting in -inactive variants that act as dominant negatives or regulators, though their prevalence and roles remain under investigation.

Protein Structure and Domains

Key Structural Domains

The BCR protein, encoded by the BCR gene, is a multidomain serine/threonine kinase consisting of 1271 amino acids and exhibiting a molecular weight of approximately 160 kDa. Its modular architecture enables diverse regulatory functions through distinct structural motifs distributed along the polypeptide chain. The N-terminal region features a coiled-coil domain spanning amino acids 1-72, which promotes protein oligomerization into homotetramers via alpha-helical interactions stabilized by hydrophobic residues at heptad positions. Adjacent to this is the central serine/threonine kinase domain, encompassing residues 72-497 and characterized by conserved catalytic motifs including an ATP-binding site (GXGXXG sequence) and substrate-binding regions that facilitate autophosphorylation and phosphorylation of serine/threonine residues on target proteins. This domain confers intrinsic kinase activity, distinguishing BCR from typical tyrosine kinases and enabling regulation of downstream signaling cascades. Further downstream, the protein includes a Dbl homology (DH) domain from 487-702, a hallmark of guanine exchange factors (GEFs) in the Dbl family, featuring alpha-helical bundles that interact with Rho-family to catalyze GDP release and promote GTP loading. This domain is biochemically coupled to a pleckstrin homology (PH) domain spanning residues 704-893, which contains a beta-sandwich fold with positively charged loops that bind phosphoinositides, thereby anchoring the protein to cellular membranes and enhancing GEF specificity. At the C-terminus lies the Rho-GTPase-activating protein (Rho-GAP) domain, covering 1004-1271, which harbors key catalytic residues such as an arginine finger that inserts into the GTPase to stabilize the for GTP hydrolysis, thereby inactivating Rho like RAC1 and CDC42. These domains collectively impart BCR with opposing regulatory capabilities toward small , balancing and inactivation in cellular signaling.

Oligomerization and Conformational Dynamics

The N-terminal region of the BCR protein features a domain that facilitates dimerization through an antiparallel arrangement of alpha-helices, enabling stable assembly essential for its regulatory functions. This domain, spanning residues 1-72, promotes homodimer formation, with from crystallographic studies showing that two such dimers can further associate into tetramers under physiological conditions, likely influencing protein stability and localization. The monomeric unit adopts a distinctive N-shaped composed of two principal alpha-helical segments, alpha-1 (residues 12-29) and alpha-2 (residues 44-63), where the N-terminal helices swap between monomers to initiate dimerization, followed by the C-terminal helices forming the core antiparallel . Crystallographic analysis of this oligomerization domain (PDB ID: 1K1F) reveals the structural basis for this assembly, with the coiled-coil interface stabilized by hydrophobic interactions and salt bridges that confer specificity for the antiparallel orientation over parallel alternatives. Biophysical characterization, including and , confirms that this configuration is thermodynamically favored, exhibiting higher thermal stability compared to engineered parallel variants. The central linker region connecting the N-terminal coiled-coil to downstream domains, such as the serine/ kinase domain, displays significant conformational flexibility, allowing dynamic adjustments that modulate access to catalytic sites and interdomain interactions. This flexibility, observed in structural models of BCR fragments, enables the protein to transition between compact and extended states, potentially regulating enzymatic activity without rigid constraints.01433-4) Oligomerization states of BCR exhibit shifts influenced by environmental factors like and post-translational modifications such as , with lower promoting dissociation from tetrameric to dimeric forms due to of key interface residues, as demonstrated by pH-dependent and sedimentation analyses. within or near the coiled-coil domain, mediated by BCR's intrinsic activity, further modulates these states by introducing charge repulsion that favors monomeric or dimeric conformations, supported by revealing dynamic interconversions and crystallographic snapshots of modified assemblies.00274-0) These regulatory mechanisms ensure adaptive responses to cellular conditions, maintaining balanced oligomer equilibria.

Physiological Functions

Enzymatic Activities

The BCR protein exhibits serine/ kinase activity primarily mediated by its N-terminal domain, enabling autophosphorylation on serine and residues as well as transphosphorylation of select substrates. This catalytic function is intrinsic to the full-length protein and contributes to its regulatory roles, with autophosphorylation occurring at multiple sites to modulate activity. In addition to kinase activity, BCR functions as a (GEF) for RhoA through its central Dbl homology (DH) domain, which accelerates the dissociation of GDP and binding of GTP to promote RhoA activation. In vitro assays demonstrate that the isolated DH domain of BCR exhibits modest GEF activity toward RhoA, facilitating nucleotide exchange in a manner dependent on the adjacent pleckstrin homology (PH) domain for membrane localization and efficiency. The C-terminal region of BCR contains a GTPase-activating protein (GAP) domain that enhances the intrinsic GTP hydrolysis rate of Rho family , particularly RAC1 and CDC42. This GAP activity converts the GTP-bound active forms of these GTPases to their inactive GDP-bound states, as evidenced by in vitro hydrolysis assays showing BCR's preference for RAC1.

Roles in Cellular Processes

The BCR gene is ubiquitously expressed across human tissues, with particularly high levels in the , hematopoietic cells, and testis, and relatively stable levels observed throughout development in the , including high concentrations in the hippocampal pyramidal cell layer and dentate gyrus, as well as moderate expression in regions such as the piriform cortex and anterior olfactory nuclei. In hematopoietic tissues like the and liver, expression is lower but consistently maintained from embryonic stages into adulthood. This tissue-specific pattern underscores BCR's involvement in processes requiring precise cytoskeletal control and in these systems. BCR plays a critical role in regulating actin cytoskeleton dynamics through its guanine nucleotide exchange factor (GEF) activity toward RhoA, which promotes the formation of and focal adhesions essential for and migration. In keratinocytes, for instance, BCR activation of RhoA drives actin remodeling and assembly, with knockdown of BCR leading to reduced RhoA-GTP levels, diminished formation, and smaller, fewer focal adhesions, thereby impairing cellular . These effects extend to broader cellular contexts, where BCR's GEF function facilitates RhoA-mediated cytoskeletal reorganization that supports directed cell movement and substrate attachment in migratory cells. BCR's serine/ kinase activity further contributes to these roles by modulating downstream signaling checkpoints. In neuronal development, BCR is essential for brain morphogenesis, as evidenced by knockout mice exhibiting structural defects in the and altered expression of Rho family , leading to impaired neuronal organization and reduced numbers in key plexuses. These phenotypes highlight BCR's contribution to RhoA-dependent cytoskeletal dynamics during neural tissue formation. Additionally, BCR's GAP activity regulates RAC1-mediated production in neutrophils and other hematopoietic cells. BCR suppresses in non-transformed cells via its kinase-mediated of AF-6, a Ras-binding protein, which downregulates Ras signaling and inhibits oncogenic transformation. This regulatory mechanism enforces , preventing unchecked growth in normal hematopoietic and neural progenitors.

Protein Interactions

Normal Binding Partners

The breakpoint cluster region (BCR) protein engages in several key interactions with adaptor and kinase proteins under normal physiological conditions, facilitating in hematopoietic and neuronal cells. BCR binds the adaptor protein through the SH2 domain of GRB2 recognizing phosphorylated 177 (pY177) on BCR, a modification that enables recruitment to signaling complexes. This interaction was demonstrated by co-immunoprecipitation (co-IP) assays in COS7 cells, where co-expression of the HCK enhanced GRB2 association with a kinase-inactive BCR construct by phosphorylating Y177. The BCR-GRB2 binding modulates Ras signaling by linking BCR to downstream effectors like , promoting GTP exchange on Ras in a controlled manner during cellular responses. BCR also interacts with the adaptor protein CRKL via proline-rich motifs in BCR's C-terminal region binding to CRKL's SH3 domains. Co-IP experiments in COS7 cells confirmed this association, showing that CRKL co-precipitates with full-length BCR independently of BCR's enzymatic activity or state. This binding contributes to cytoskeletal and signaling in hematopoietic cells, with yeast two-hybrid screens and co-IP validating similar interactions in physiological contexts. BCR directly interacts with the HCK, preferentially binding its inactive conformation (e.g., via regulatory tyrosines) in a kinase-independent manner. Co-IP in 32D myeloid cells and COS7 cells showed enhanced association upon HCK , leading to HCK activation and subsequent of BCR at Y177. This partnership influences function by coordinating signaling and cytoskeletal dynamics in immune cells.

Dysregulated Interactions

In non-oncogenic contexts, dysregulated BCR protein interactions contribute to pathological states by altering signaling and cytoskeletal dynamics, distinct from its normal associations with partners like CRKL that maintain steady-state cellular regulation. BCR associates with the α subunit of casein kinase II (CK2α), which is required for BCR-mediated inflammation in macrophages through activation of (PI3K) and (NF-κB) pathways, independent of BCR's kinase activity. This leads to enhanced production and inflammatory responses. BCR knockdown reduces this inflammatory signaling. In neuronal contexts, BCR interacts with NMDA receptors alongside Tiam1, differentially regulating Rac1 GAP activity in response to , which is dysregulated in conditions affecting hippocampal function. Mutations in BCR, such as loss-of-function variants, are associated with neurodevelopmental defects including malformations, , and gastrointestinal dysmotility, likely due to impaired regulation of Rho during development.

Role in Disease

BCR-ABL Fusion and Oncogenesis

The BCR-ABL fusion gene arises from the reciprocal translocation t(9;22)(q34;q11), known as the , which juxtaposes the BCR gene on with the ABL1 gene on 9. This chromosomal abnormality results in the production of a chimeric BCR-ABL protein, predominantly the p210 isoform in chronic myeloid leukemia (CML), encoded by e13a2 (b2a2) or e14a2 (b3a2) fusion transcripts depending on the precise in the major breakpoint cluster region (M-BCR) of BCR. The fusion disrupts the normal regulatory domains of ABL1, leading to its oncogenic activation. The N-terminal coiled-coil oligomerization domain of BCR in the promotes dimerization and higher-order oligomerization of BCR-ABL, which brings the ABL1 domains into close proximity and induces constitutive activity independent of upstream stimuli. This oligomerization facilitates autophosphorylation of key tyrosine residues on BCR-ABL, including Tyr-177 in the BCR portion, which serves as a docking site for adaptor proteins like , thereby amplifying downstream signaling. Unlike wild-type ABL1, which is autoinhibited by its SH3 domain and requires ligand binding for , the BCR-ABL fusion lacks these inhibitory mechanisms, resulting in persistent signaling that drives leukemogenesis. Constitutive BCR-ABL activity triggers multiple downstream pathways, including JAK-STAT (notably STAT5 phosphorylation for enhanced transcription of survival genes), PI3K/AKT (promoting cell survival by inhibiting pro-apoptotic proteins like BAD), and RAS/MAPK (driving expression and progression). These pathways collectively enhance cellular proliferation, inhibit , and impair , contributing to the uncontrolled expansion of leukemic cells characteristic of Philadelphia chromosome-positive leukemias. Variant BCR-ABL fusions occur based on breakpoint locations within BCR. The p190 isoform, predominant in chromosome-positive (ALL), results from breakpoints in the minor breakpoint cluster region (m-BCR, typically after 1), producing the e1a2 transcript and retaining more of the BCR oligomerization domain for heightened activity compared to p210. In contrast, rare p230 fusions from the μ-BCR (after 19) are associated with neutrophilic leukemias and exhibit milder oncogenic potential due to inclusion of additional BCR regulatory elements. These isoform differences influence disease , with p190 driving more lymphoid-biased transformation.

Associations with Other Pathologies

Beyond its well-characterized role in BCR-ABL fusions, the BCR gene participates in other oncogenic rearrangements, such as BCR-FGFR1 fusions observed in 8p11 myeloproliferative syndrome (EMS), a rare and aggressive hematological . These fusions, typically resulting from t(8;22)(p11;q11) translocations, juxtapose the dimerization domain of BCR with the domain of FGFR1, leading to constitutive activation of FGFR signaling pathways that promote uncontrolled and survival. This aberrant activity mirrors the oncogenic mechanisms seen in classic BCR fusions but drives a distinct myeloproliferative phenotype with rapid progression to . The BCR gene also encodes the renal carcinoma antigen NY-REN-26, recognized by autologous antibodies in patients with (RCC). This is derived from the BCR protein and has been identified through serological analysis of recombinant cDNA expression libraries (SEREX) from RCC tumor tissues, highlighting its in the context of clear cell RCC. In (GBM), BCR-ABL-like fusions, including canonical BCR-ABL1 rearrangements, have been reported, expanding the spectrum of BCR involvement in solid tumors. RNA sequencing in GBM cases has revealed such fusions, which activate downstream signaling akin to those in hematological malignancies, potentially enhancing tumor aggressiveness. Outside of , genetic variants near the BCR gene have been implicated in non-cancer pathologies through genome-wide association studies (GWAS). A schizophrenia-associated (SNP) located approximately 26 kb upstream of BCR influences enhancer activity in neural cells, altering and potentially disrupting synaptic function or neurodevelopment. This variant, identified in large-scale GWAS consortia, highlights BCR's broader role in psychiatric risk, with functional assays demonstrating its impact on chromatin accessibility and transcription in brain-relevant cell types.

Clinical and Therapeutic Implications

Diagnostic and Prognostic Applications

The detection of BCR-ABL fusion transcripts is a cornerstone of diagnosing chronic myeloid leukemia (CML), primarily achieved through (FISH) and (RT-PCR). FISH identifies BCR::ABL1 rearrangements in interphase nuclei of peripheral blood or cells, offering high sensitivity for confirming the and its variants, with detection rates approaching 100% in typical cases when combined with cytogenetic analysis. RT-PCR, particularly qualitative assays targeting common transcripts like e13a2 and e14a2, complements FISH by detecting BCR-ABL1 mRNA with sensitivities exceeding 95% for these transcripts in newly diagnosed CML patients, enabling precise identification of fusion types essential for subsequent monitoring. These methods are recommended by the European LeukemiaNet for all suspected CML cases to establish the alongside conventional , as they reliably detect the fusion even in cryptic or variant translocations; the 2025 ELN recommendations reaffirm these standards. For ongoing patient management, quantitative PCR (qPCR) is employed to monitor minimal residual disease (MRD) by measuring BCR-ABL1/ABL1 transcript ratios on the International Scale (IS), which standardizes results across laboratories relative to a baseline of 100% at diagnosis. Key thresholds include an early molecular response (EMR) of ≤10% IS at 3 months, indicating optimal initial response to therapy, and a major molecular response (MMR) of ≤0.1% IS by 12 months, associated with improved progression-free survival. Deeper responses, such as ≤0.01% IS (MR4.0), further correlate with long-term remission and eligibility for treatment discontinuation trials, with qPCR sensitivity reaching 10^-5 or better for low-level detection. This approach allows for risk-adapted management, where failure to achieve these milestones prompts evaluation for resistance. The 2025 ELN guidelines confirm these monitoring thresholds without major changes. Prognostic stratification in BCR-ABL-positive malignancies incorporates additional cytogenetic abnormalities (ACAs) identified at diagnosis, which signal genomic instability and poorer outcomes beyond the fusion itself. For instance, major-route ACAs like trisomy 8 (+8) are frequent in CML but often do not worsen prognosis when occurring alone, unlike high-risk ACAs such as i(17q) or +Ph, which promote clonal evolution and reduce survival. These require routine assessment via karyotyping or FISH to guide intensified monitoring.

Targeted Therapies and Emerging Research

Targeted therapies for BCR-ABL-driven malignancies primarily revolve around inhibitors (TKIs) that disrupt the oncogenic signaling of the . , the first-generation TKI and standard first-line treatment for chronic myeloid leukemia (CML), exhibits an of approximately 0.1 μM against BCR-ABL, effectively inhibiting its activity and inducing durable responses in the majority of patients. For cases resistant to due to mutations or other mechanisms, second-generation TKIs such as and are employed, offering improved potency and broader activity against certain BCR-ABL mutants while maintaining efficacy in frontline settings. Third-generation TKIs, exemplified by , address resistance conferred by the T315I gatekeeper mutation, which renders earlier agents ineffective. potently inhibits T315I-mutated BCR-ABL and has demonstrated significant clinical benefit in resistant CML, contributing to overall 5-year survival rates exceeding 90% in CML patients treated with TKIs, including those with challenging mutations (as of 2025). Recent advancements include allosteric inhibitors like (ABL001), which targets the myristoyl pocket of ABL1 to lock BCR-ABL in an inactive conformation, bypassing ATP-site resistance. received FDA approval for frontline treatment of newly diagnosed chronic-phase CML in based on phase 3 data showing superior major molecular response rates compared to , and it has demonstrated efficacy in heavily pretreated patients. Additionally, proteolysis-targeting chimeras (PROTACs) have emerged as a promising preclinical strategy for BCR-ABL degradation; novel PROTACs induce ubiquitin-mediated proteasomal breakdown of both wild-type and mutant forms in nanomolar concentrations, overcoming limitations of traditional TKIs in models of CML (no clinical trials as of 2025). Emerging research emphasizes combination approaches to enhance outcomes, particularly in chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Clinical trials, such as NCT06124157, are investigating the integration of TKIs like or with agents including alongside , aiming to improve response rates and negativity in newly diagnosed Ph+ ALL patients. These strategies seek to deepen remissions and reduce relapse risk, with ongoing studies from 2023 onward reporting enhanced tolerability in frontline and relapsed settings.

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