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The updated International Consensus Classification (ICC) of B-acute lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL) includes both revisions to subtypes previously outlined in the 2016 WHO classification and several newly described entities. The ICC classification incorporates recent clinical, cytogenetic, and molecular data, with a particular emphasis on whole transcriptome analysis and gene expression (GEX) clustering studies. B-ALL classification is modified to further subclassify BCR::ABL1-positive B-ALL and hypodiploid B-ALL. Additionally, nine new categories of B-ALL are defined, including seven that contain distinguishing gene rearrangements, as well as two new categories that are characterized by a specific single gene mutation. Four provisional entities are also included in the updated B-ALL classification, although definitive identification of these subtypes requires GEX studies. T-ALL classification is also updated to incorporate BCL11B-activating rearrangements into early T-precursor (ETP) ALL taxonomy. Additionally, eight new provisional entities are added to the T-ALL subclassification. The clinical implications of the new entities are discussed, as are practical approaches to the use of different technologies in diagnosis. The enhanced specificity of the new classification will allow for improved risk stratification and optimized treatment plans for patients with ALL.

A new pathway for the processing of β-amyloid precursor protein (APP) is described in which η-secretase activity, in part mediated by the MT5-MMP metalloproteinase, cleaves APP, and further processing by ADAM10 and BACE1 generates proteolytic fragments capable of inhibiting long-term potentiation in the hippocampus. Neuronal inhibition by APP by-products Michael Willem et al . describe a previously unknown pathway for the processing of β-amyloid precursor protein (APP) in which η-secretase cleaves APP to yield a soluble C-terminal fragment termed CTF-η. The soluble fragment, sAPP-η can be further processed by ADAM10 and BACE1 to generate the peptides Aη-α and Aη-β respectively, which are capable of inhibiting long-term potentiation in the hippocampus. The relevant η-secretase activity is largely due to the membrane-bound matrix metalloproteinase, MT5-MMP, whose activity is enriched in dystrophic neurites in a mouse model of Alzheimer's disease and in the brains of Alzheimer's patients. Genetic or pharmacological inhibition of BACE1 results in increased accumulation of both CTF-η and Aη-α. This work suggests that BACE 1-based therapies may result in the generation of another potentially toxic substance (Aη-α) and that therapeutic inhibition of BACE1 activity requires careful titration. Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide 1 . Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner 1 . Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo 2 . Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504–505 of APP 695 , releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-β). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo , long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.

Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by reciprocal chromosomal translocation between chromosome 9 and 22, leading to the expression of constitutively active oncogenic BCR–ABL1 fusion protein. CXC chemokine receptor 4 (CXCR4) is essential for the survival of BCR–ABL1-transformed mouse pre-B cells, as the deletion of CXCR4 induces death in these cells. To investigate whether CXCR4 inhibition also effectively blocks BCR–ABL1-transformed cell growth in vitro, in this study, we explored an array of peptide-based inhibitors of CXCR4. The inhibitors were optimized derivatives of EPI-X4, an endogenous peptide antagonist of CXCR4. We observed that among all the candidates, EPI-X4 JM#170 (referred to as JM#170) effectively induced cell death in BCR–ABL1-transformed mouse B cells but had little effect on untransformed wild-type B cells. Importantly, AMD3100, a small molecule inhibitor of CXCR4, did not show this effect. Treatment with JM#170 induced transient JNK phosphorylation in BCR–ABL1-transformed cells, which in turn activated the intrinsic apoptotic pathway by inducing cJun, Bim, and Bax gene expressions. Combinatorial treatment of JM#170 with ABL1 kinase inhibitor Imatinib exerted a stronger killing effect on BCR–ABL1-transformed cells even at a lower dose of Imatinib. Surprisingly, JM#170 actively killed Sup-B15 cells, a BCR–ABL1+ human ALL cell line, but had no effect on the BCR–ABL1− 697 cell line. This suggests that the inhibitory effect of JM#170 is specific for BCR–ABL1+ ALL. Taken together, JM#170 emerges as a potent novel drug against Ph+ ALL.

Several lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) could correspond to an etiological trigger of Alzheimer’s disease (AD) pathology. Altered mitochondrial homeostasis is considered an early event in AD development. However, the specific contribution of APP-CTFs to mitochondrial structure, function, and mitophagy defects remains to be established. Here, we demonstrate in neuroblastoma SH-SY5Y cells expressing either APP Swedish mutations, or the β-secretase-derived APP-CTF fragment (C99) combined with β- and γ-secretase inhibition, that APP-CTFs accumulation independently of Aβ triggers excessive mitochondrial morphology alteration (i.e., size alteration and cristae disorganization) associated with enhanced mitochondrial reactive oxygen species production. APP-CTFs accumulation also elicit basal mitophagy failure illustrated by enhanced conversion of LC3, accumulation of LC3-I and/or LC3-II, non-degradation of SQSTM1/p62, inconsistent Parkin and PINK1 recruitment to mitochondria, enhanced levels of membrane and matrix mitochondrial proteins, and deficient fusion of mitochondria with lysosomes. We confirm the contribution of APP-CTFs accumulation to morphological mitochondria alteration and impaired basal mitophagy in vivo in young 3xTgAD transgenic mice treated with γ-secretase inhibitor as well as in adeno-associated-virus-C99 injected mice. Comparison of aged 2xTgAD and 3xTgAD mice indicates that, besides APP-CTFs, an additional contribution of Aβ to late-stage mitophagy activation occurs. Importantly, we report on mitochondrial accumulation of APP-CTFs in human post-mortem sporadic AD brains correlating with mitophagy failure molecular signature. Since defective mitochondria homeostasis plays a pivotal role in AD pathogenesis, targeting mitochondrial dysfunctions and/or mitophagy by counteracting early APP-CTFs accumulation may represent relevant therapeutic interventions in AD.

We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19 – relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach. Mutations in the CD19 gene suggesting irreversible loss of its surface expression are identified in the majority of analyzed cases of CD19 – relapse in two clinical trials of pediatric ALL CD19 CAR T therapy, offering considerations for the rational choice of follow-up therapies.

Alzheimer’s disease (AD) is caused by synaptic and neuronal loss in the brain. One of the characteristic hallmarks of AD is senile plaques containing amyloid β-peptide (Aβ). Aβ is produced from amyloid precursor protein (APP) by sequential proteolytic cleavages by β-secretase and γ-secretase, and the polymerization of Aβ into amyloid plaques is thought to be a key pathogenic event in AD. Since γ-secretase mediates the final cleavage that liberates Aβ, γ-secretase has been widely studied as a potential drug target for the treatment of AD. γ-Secretase is a transmembrane protein complex containing presenilin, nicastrin, Aph-1, and Pen-2, which are sufficient for γ-secretase activity. γ-Secretase cleaves >140 substrates, including APP and Notch. Previously, γ-secretase inhibitors (GSIs) were shown to cause side effects in clinical trials due to the inhibition of Notch signaling. Therefore, more specific regulation or modulation of γ-secretase is needed. In recent years, γ-secretase modulators (GSMs) have been developed. To modulate γ-secretase and to understand its complex biology, finding the binding sites of GSIs and GSMs on γ-secretase as well as identifying transiently binding γ-secretase modulatory proteins have been of great interest. In this review, decades of findings on γ-secretase in AD are discussed.Alzheimer’s disease: changing activity of critical enzyme offers therapeutic optionDrugs that only affect the activity of an enzyme called γ-secretase but do not entirely block its function could provide a safer therapeutic option for preventing the build-up of toxic proteins in the brain linked to AD. Dr. Ji-Yeun Hur from Memorial Sloan Kettering Cancer Center, New York, USA, discusses the functions of γ-secretase, which include cleaving amyloid precursor proteins into smaller fragments that can aggregate to form sticky plaques, and reviews attempts to develop therapies directed against the enzyme. Early drug candidates proved too toxic because they blocked all functions of γ-secretase including desirable functions, leading to side effects. Newer drug strategies have focused on changing how γ-secretase processes Alzheimer’s-related proteins without disrupting its other physiological functions. A better understanding of γ-secretase’s complex structure and various functions could inform those strategies.

This study shows that, despite malignant transformation, autoimmune checkpoints are still functional in B-cell leukaemia, with targeted activation of these checkpoints effectively killing patient-derived B-cell leukaemia in a transplant model; the results represent a novel strategy to overcome drug resistance in leukaemia patients. Anticancer action of excess BCR signalling Markus Müschen and colleagues reason that in certain B cell malignancies with constitutive B cell receptor (BCR) signalling — acute lymphoblastic leukaemias carrying BCR–ABL translocations — it may be possible to modify the normal selection process that favours B cells with an intermediate level of BCR signalling to instead drive BCR signalling over a threshold at which malignant B cells fail to survive. They show that this can be achieved by hyperactivation of the kinase SYK, for example, in a mouse model where pharmacological activation of a SYK pathway reduces the growth of patient-derived tumour xenografts. This concept is distinct from approaches to B lymphoma therapies that seek to block BCR signalling, and may be worth exploring in the clinic. B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR) 1 or hyperactivation above maximum (for example, self-reactive BCR) 2 , 3 thresholds of signalling strength causes negative selection. In ∼25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling 4 , 5 . Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival 6 . We tested the hypothesis that targeted hyperactivation—above a maximum threshold—will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR–ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1 , Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7 ) and Inpp5d (ref. 8 ). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1) 9 , we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL.

Tissue-resident macrophages support embryonic development and tissue homeostasis and repair. The mechanisms that control their differentiation remain unclear. We report here that erythro-myeloid progenitors in mice generate premacrophages (pMacs) that simultaneously colonize the whole embryo from embryonic day 9.5 in a chemokine-receptor–dependent manner. The core macrophage program initiated in pMacs is rapidly diversified as expression of transcriptional regulators becomes tissue-specific in early macrophages. This process appears essential for macrophage specification and maintenance, as inactivation of Id3 impairs the development of liver macrophages and results in selective Kupffer cell deficiency in adults. We propose that macrophage differentiation is an integral part of organogenesis, as colonization of organ anlagen by pMacs is followed by their specification into tissue macrophages, hereby generating the macrophage diversity observed in postnatal tissues.

Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by leukemic blasts presenting myeloid and lymphoid markers. Here we report data from integrated genomic analysis on 31 MPAL samples and compare molecular profiling with that from acute myeloid leukemia (AML), B cell acute lymphoblastic leukemia (B-ALL), and T cell acute lymphoblastic leukemia (T-ALL). Consistent with the mixed immunophenotype, both AML-type and ALL-type mutations are detected in MPAL. Myeloid-B and myeloid-T MPAL show distinct mutation and methylation signatures that are associated with differences in lineage-commitment gene expressions. Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated with better clinical response when lineage-matched therapy is given. These results elucidate the genetic and epigenetic heterogeneity of MPAL and its genetic distinction from AML, B-ALL, and T-ALL and further provide proof of concept for a molecularly guided precision therapy approach in MPAL. Mixed phenotype acute leukemia (MPAL) is a rare leukemia that presents both myeloid and lymphoid markers on blasts. Here the authors perform genomic analysis to show MPAL involves genetic and epigenetic heterogeneity and is genetically distinct from AML, B-ALL, and T-ALL.

ABSTRACT T‐cell acute lymphoblastic leukemia (T‐ALL) is a clonal proliferative malignant disease characterized by abnormal T‐cell development. The classification of T‐ALL primarily hinges on immunophenotype, encompassing early T‐cell precursor (ETP)‐ALL, near‐ETP‐ALL, and non‐ETP‐ALL. We summarized clinical information from 117 patients, with genetic data available for 77 patients and transcriptomic data available for 24 patients. An ETP‐like score model was established based on transcriptome, aiming to address the subjectivity in the current T‐ALL immunophenotype classification. The retrospective analysis indicated that ETP immunophenotype was not a prognostic factor for T‐ALL patients. Compared to non‐ETP‐ALL patients, ETP‐like patients including ETP‐ALL and near‐ETP‐ALL were more likely to carry MED12 gene mutations, which may predict a dismal outcome. Transcriptomic analysis suggested that T‐ALL patients with different immunophenotypes were in accordance with the T‐cell development trajectory, while ETP‐like patients exhibited characteristics of early T‐cell development. Finally, we established an ETP‐like score model and confirmed its efficiency across four independent cohorts, with sensitivity exceeding 80%. And T‐ALL patients with high ETP‐like score were associated with poor prognosis. In conclusion, our study elucidated the clinical and molecular features of distinct subtypes of T‐ALL patients, providing new valuable insights for T‐ALL classification. This study categorized T‐ALL patients into 3 distinct subgroups: ETP‐like group, immature T‐ALL group, and mature T‐ALL group based on transcriptome. ETP‐like patients exhibited characteristics of early T‐cell development, which can be identified by the ETP‐like score model.