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Case Report: Multi-Omics Analysis and CAR-T Treatment of a Chronic Myeloid Leukemia Blast Crisis Case 5 Years After the Discontinuation of TKI.

ABSTRACT: Most relapsed chronic myeloid leukemia (CML) patients after tyrosine kinase inhibitor (TKI) discontinuation are in a chronic phase and could achieve remission through restarting the TKI treatment. Here we reported a case of sudden lymphoid blast crisis after 67 months of TKI discontinuation and depicted the patient by DNA and RNA sequencing to investigate intrinsic molecular features. The mutations of TGFBR2 and PCNT and the dysregulations of TGF-β and other pathways might accelerate the B cell transformation, which may serve as a blast crisis risk indicator of CML. Single-cell transcriptome data revealed that several clusters of immature B cells and late pro-B cells presented clone evolution during the treatment. After failing multiple lines of TKIs, conditioning chemotherapies and chimeric antigen receptor T cells (CAR-T) targeting CD19 and CD22 were performed to achieve remission. In conclusion, we report the first case of a CML patient with sudden lymphoid blast crisis after a long treatment-free remission and additional gene abnormalities other than BCR-ABL1 might participate in the progression, which need to be closely monitored, and CAR-T could be a solution to the chemoresistant progression.

SUBMITTER: Miao YR

PROVIDER: S-EPMC8490701 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Leukemia Blast Crisis: A Simulation Case for Residents.

Project description:IntroductionOncologic emergencies are life-threatening and often require advanced team-management skills as well as a mastery of disease processes and therapeutic interventions. Simulation of an oncologic emergency case is a useful way to experience, reflect on, and practice these skills. This case involving a simulated patient in blast crisis was created as part of our Emergency Medicine (EM) Resident Simulation Curriculum at the Perelman School of Medicine at the University of Pennsylvania.MethodsThis case is based on an actual patient seen in our emergency department and highlights specific teaching points and potential pitfalls in treatment algorithms. It details a 40-year-old female with history of acute myeloid leukemia presenting with fatigue for 2 days, tachycardia, and labored breathing. The patient develops worsening respiratory distress if not intervened upon and progresses to pulseless electrical activity arrest. Lab work is notable for markedly elevated white blood cell count and acidosis. A SimMan or SimMan3G is required for the simulation. The associated debriefing materials are Included in this educational resource. Evaluation of learner performance is mapped to the EM Milestones.ResultsEighteen of the 20 (90%) EM residents that participated in this simulation, responded to the Likert-scale postsession survey. Of those who responded, 83% agreed or strongly agreed that the case was realistic and 89% agreed or strongly agreed that the case was useful.DiscussionThe simulation venue offers a unique opportunity to address team dynamics as well as provide a forum for didactic learning as it is often difficult to debrief a critical case while working in real-time patient care settings.

| S-EPMC6440397 | biostudies-literature

Histone demethylase RBP2 decreases miR-21 in blast crisis of chronic myeloid leukemia.

Project description:Chronic myeloid leukemia in the blastic phase (CML-BP) responds poorly to clinical treatments and is usually fatal. In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP. The RBP2 histone demethylase stimulates leukemia cell differentiation and inhibits cell proliferation. We identified miR-21 was directly downregulated by RBP2 and found that miR-21 downregulated PDCD4 expression in leukemia cells. By binding to miR-21 promoter and by demethylating of trimethylated H3K4 at the miR-21 locus, RBP2 downregulated miR-21 expression. This in turn activated PDCD4. In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML.

| S-EPMC4359230 | biostudies-other

Blast crisis Ph+ chronic myeloid leukemia with NUP98/HOXA13 up-regulating MSI2.

Project description:BackgroundMusashi2(Msi2)-Numb pathway de-regulation is a molecular mechanism underlying the transition of chronic phase Ph + CML to deadly blast crisis, particularly in cases with a NUP98/HOXA9 fusion from a t(7;11)(p15;p15). This study provides new insights on the mechanisms cooperating in driving MSI2 over-expression and progression of Ph-positive CML.ResultsHerein we describe a t(7;11)(p15;p15) originating a NUP98 fusion with HOXA13, at 7p15, in a 39 year-old man in blast crisis of Ph-positive CML. Both MSI2 and HOXA9 were evaluated by quantitative RT-PCR in our patient and in a series of haematological malignancies. Up-regulation of both genes emerged only in the presence of NUP98/HOXA13 gene fusion. However, over-expression of MSI2, but not HOXA9, was found in 2 cases of Ph + blast crisis with additional chromosome aberrations other than t(7;11). To determine the mechanisms underlying MSI2 over-expression in our patient we performed Chromatin Immunoprecipitation and found that NUP98/HOXA13 fusion protein deregulates MSI2 gene by binding its promoter.ConclusionsTo the best of our knowledge, this is the first molecular characterization of NUP98/HOXA13 fusion in blast crisis of Ph + CML. Our findings suggest cooperative mechanisms of MSI2 over-expression driven by HOXA proteins and strongly supports MSI2 as a prognostic marker and a candidate in target treatment of CML.

| S-EPMC4071805 | biostudies-literature

Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function.

Project description:Chronic myeloid leukemia responds well to therapy targeting the oncogenic fusion protein BCR-ABL1 in chronic phase, but is resistant to treatment after it progresses to blast crisis (BC). BC is characterized by elevated ?-catenin signaling in granulocyte macrophage progenitors (GMPs), which enables this population to function as leukemia stem cells (LSCs) and act as a reservoir for resistance. Because normal hematopoietic stem cells (HSCs) and LSCs depend on ?-catenin signaling for self-renewal, strategies to specifically target BC will require identification of drugable factors capable of distinguishing between self-renewal in BC LSCs and normal HSCs. Here, we show that the MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis is overexpressed in BC GMPs but not normal HSCs, and that MNK kinase-dependent eIF4E phosphorylation at serine 209 activates ?-catenin signaling in BC GMPs. Mechanistically, eIF4E overexpression and phosphorylation leads to increased ?-catenin protein synthesis, whereas MNK-dependent eIF4E phosphorylation is required for nuclear translocation and activation of ?-catenin. Accordingly, we found that a panel of small molecule MNK kinase inhibitors prevented eIF4E phosphorylation, ?-catenin activation, and BC LSC function in vitro and in vivo. Our findings identify the MNK-eIF4E axis as a specific and critical regulator of BC self-renewal, and suggest that pharmacologic inhibition of the MNK kinases may be therapeutically useful in BC chronic myeloid leukemia.

| S-EPMC3690864 | biostudies-other

A multicellular basis for the origination of blast crisis in chronic myeloid leukemia.

Project description:Chronic myeloid leukemia (CML) is characterized by a specific chromosome translocation, and its pathobiology is considered comparatively well understood. Thus, quantitative analysis of CML and its progression to blast crisis may help elucidate general mechanisms of carcinogenesis and cancer progression. Hitherto, it has been widely postulated that CML blast crisis originates mainly via cell-autonomous mechanisms such as secondary mutations or genomic instability. However, recent results suggest that carcinogenic transformation may be an inherently multicellular event, in departure from the classic unicellular paradigm. We investigate this possibility in the case of blast crisis origination in CML. A quantitative, mechanistic cell population dynamics model was employed. This model used recent data on imatinib-treated CML; it also used earlier clinical data, not previously incorporated into current mathematical CML/imatinib models. With the pre-imatinib data, which include results on many more blast crises, we obtained evidence that the driving mechanism for blast crisis origination is a cooperation between specific cell types. Assuming leukemic-normal interactions resulted in a statistically significant improvement over assuming either cell-autonomous mechanisms or interactions between leukemic cells. This conclusion was robust with regard to changes in the model's adjustable parameters. Application of the results to patients treated with imatinib suggests that imatinib may act not only on malignant blast precursors, but also, to a limited degree, on the malignant blasts themselves.

| S-EPMC3537493 | biostudies-literature

Understanding and Monitoring Chronic Myeloid Leukemia Blast Crisis: How to Better Manage Patients.

Project description:Chronic myeloid leukemia (CML) is triggered primarily by the t(9;22) (q34.13; q11.23) translocation. This reciprocal chromosomal translocation leads to the formation of the BCR-ABL fusion gene. Patients in the chronic phase (CP) experience a good curative effect with tyrosine kinase inhibitors. However, cases are treatment refractory, with a dismal prognosis, when the disease has progressed to the accelerated phase (AP) or blast phase (BP). Until now, few reports have provided a comprehensive description of the mechanisms involved at different molecular levels. Indeed, the underlying pathogenesis of CML evolution comprises genetic aberrations, chromosomal translocations (except for the Philadelphia chromosome), telomere biology, and epigenetic anomalies. Herein, we provide knowledge of the biology responsible for blast transformation of CML at several levels, such as genetics, telomere biology, and epigenetic anomalies. Because of the limited treatment options available and poor outcomes, only the therapeutic response is monitored regularly, which involves BCR-ABL transcript level assessment and immunologic surveillance, with the optimal treatment strategy for patients in CP adapted to evaluate disease recurrence or progression. Overall, selecting optimal treatment endpoints to predict survival and successful TFR improves the quality of life of patients. Thus, identifying risk factors and developing risk-adapted therapeutic options may contribute to a better outcome for advanced-phase patients.

| S-EPMC8236273 | biostudies-literature

Histone chaperone ASF1A accelerates chronic myeloid leukemia blast crisis by activating Notch signaling.

Project description:The blast crisis (BC) is the final deadly phase of chronic myeloid leukemia (CML), which remains a major challenge in clinical management. However, the underlying molecular mechanism driving blastic transformation remains unclear. Here, we show that ASF1A, an essential activator, enhanced the transformation to CML-BC by mediating cell differentiation arrest. ASF1A expression was aberrantly increased in bone marrow samples from CML-BC patients compared with newly diagnosed CML-chronic phase (CP) patients. ASF1A inhibited cell differentiation and promoted CML development in vivo. Mechanistically, we identified ASF1A as a coactivator of the Notch transcriptional complex that induces H3K56ac modification in the promoter regions of Notch target genes, and subsequently enhanced RBPJ binding to these promoter regions, thereby enhancing Notch signaling activation to mediate differentiation arrest in CML cells. Thus, our work suggests that targeting ASF1A might represent a promising therapeutic approach and a biomarker to detect disease progression in CML patients.

| S-EPMC9527247 | biostudies-literature

miR-181d/RBP2/NF-κB p65 Feedback Regulation Promotes Chronic Myeloid Leukemia Blast Crisis.

Project description:BackgroundChronic myeloid leukemia (CML) is a malignant clonal proliferative disease. Once it progresses into the phase of blast crisis (CML-BP), the curative effect is poor, and the fatality rate is extremely high. Therefore, it is urgent to explore the molecular mechanisms of blast crisis and identify new therapeutic targets.MethodsThe expression levels of miR-181d, RBP2 and NF-κB p65 were assessed in 42 newly diagnosed CML-CP patients and 15 CML-BP patients. Quantitative real-time PCR, Western blots, and cell proliferation assay were used to characterize the changes induced by overexpression or inhibition of miR-181d, RBP2 or p65. Luciferase reporter assay and ChIP assay was conducted to establish functional association between miR-181d, RBP2 and p65. Inhibition of miR-181d expression and its consequences in tumor growth was demonstrated in vivo models.ResultsWe found that miR-181d was overexpressed in CML-BP, which promoted leukemia cell proliferation. Histone demethylase RBP2 was identified as a direct target of miR-181d which downregulated RBP2 expression. Moreover, RBP2 inhibited transcriptional expression of NF-κB subunit, p65 by binding to its promoter and demethylating the tri/dimethylated H3K4 region in the p65 promoter locus. In turn, p65 directly bound to miR-181d promoter and upregulated its expression. Therefore, RBP2 inhibition resulting from miR-181d overexpression led to p65 upregulation which further forwarded miR-181d expression. This miR-181d/RBP2/p65 feedback regulation caused sustained NF-κB activation, which contributed to the development of CML-BP.ConclusionsTaken together, the miR-181d/RBP2/p65 feedback regulation promoted CML-BP and miR-181d may serve as a potential therapeutic target of CML-BP.

| S-EPMC8027495 | biostudies-literature

Myodesopsia is a symptom of central nervous system blast crisis in chronic myeloid leukemia.

Project description:A 49-year-old woman diagnosed with chronic myeloid leukemia in the chronic phase was started on dasatinib treatment, after which she complained of myodesopsia. Nineteen months after diagnosis, the patient again complained of myodesopsia and developed bilateral optic neuritis. Cerebrospinal fluid analysis revealed an increase in blasts, although peripheral blood and bone marrow examination confirmed that the patient remained in a molecular response to tyrosine kinase inhibitor (TKI) therapy. The patient was diagnosed with an isolated central nervous system blast crisis, a rare occurrence with second-generation TKI therapy, and the initial presentation of myodesopsia represented a symptom of this condition.

| S-EPMC6416525 | biostudies-literature

Modeling Blast Crisis Using Mutagenized Chronic Myeloid Leukemia-Derived Induced Pluripotent Stem Cells (iPSCs).

Project description:PurposeTo model CML progression in vitro and generate a blast crisis (BC-CML) model in vitro in order to identify new targets.MethodsThree different CML-derived iPSC lines were mutagenized with the alkylating agent ENU on a daily basis for 60 days. Cells were analyzed at D12 of hematopoietic differentiation for their phenotype, clonogenicity, and transcriptomic profile. Single-cell RNA-Seq analysis has been performed at three different time points during hematopoietic differentiation in ENU-treated and untreated cells.ResultsOne of the CML-iPSCs, compared to its non-mutagenized counterpart, generated myeloid blasts after hematopoietic differentiation, exhibiting monoblastic patterns and expression of cMPO, CD45, CD34, CD33, and CD13. Single-cell transcriptomics revealed a delay of differentiation in the mutated condition as compared to the control with increased levels of MSX1 (mesodermal marker) and a decrease in CD45 and CD41. Bulk transcriptomics analyzed along with the GSE4170 GEO dataset reveal a significant overlap between ENU-treated cells and primary BC cells. Among overexpressed genes, CD25 was identified, and its relevance was confirmed in a cohort of CML patients.ConclusionsiPSCs are a valuable tool to model CML progression and to identify new targets. Here, we show the relevance of CD25 identified in the iPSC model as a marker of CML progression.

| S-EPMC9953961 | biostudies-literature

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