News - MPL W515L - LARVOL VERI

2ms

In vivo ablation of NFκB cascade effectors alleviates disease burden in myeloproliferative neoplasms. (PubMed, Blood)

Finally, pharmacological targeting of interleukin-1 receptor-associated kinase 4 (IRAK4) with inhibitor CA-4948 suppressed disease burden and inflammatory cytokines specifically in MPN without inducing toxicity in non-diseased models. These findings highlight vulnerabilities in MPN that are exploitable with emerging therapeutic approaches.

2 months ago

Preclinical • Journal

MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4) • RELA (RELA Proto-Oncogene)

MPL W515L

emavusertib (CA-4948)

5ms

Expanded molecular detection of MPL codon p.W515 and p.S505N mutations in myeloproliferative neoplasms. (PubMed, J Clin Lab Anal)

Current MPL assays are predominantly focused on p.W515L/K and p.S505N mutations. We have engineered an MPL test for detecting p.W515A/L/K/R and p.S505N variants, thereby increasing the diagnostic yield with little additional expense or technician time.

5 months ago

Journal

JAK2 (Janus kinase 2)

JAK2 V617F • MPL W515L

6ms

SHP2 Inhibition Enhances JAK2 Inhibitor Therapy in Preclinical Models of Myeloproliferative Neoplasms (ASH 2023)

We found that the SHP2 inhibitors RMC-4550 and SHP099 enhanced growth inhibition of MPN model cell lines (e.g., SET2 and UKE1) in combination with ruxolitinib, effectively preventing ruxolitinib persistent growth. Importantly, the combination of SHP2 inhibition using RMC-4550 with JAK2 inhibition using ruxolitinib for 4 weeks in wildtype mice was well tolerated with respect to hematologic parameters and exemplified by no effect on body weight (Panel B). Given SHP2 inhibitors are already undergoing clinical evaluation in patients with solid tumors, our findings suggest that SHP2 is a therapeutic target with potential to be rapidly translated to clinical assessment for MPN patients.

6 months ago

Preclinical

TNFA (Tumor Necrosis Factor-Alpha) • CXCL9 (Chemokine (C-X-C motif) ligand 9) • CALR (Calreticulin) • IL1B (Interleukin 1, beta)

MPL W515L

Jakafi (ruxolitinib) • SHP099 • RMC-4550

6ms

Upregulation of Platelet Transcripts As Biomarkers of Fibrotic Progression in Myeloproliferative Neoplasms (ASH 2023)

For MPN patients, a deviation from steady-state platelet transcript levels, specifically for H2AFX and CEP55, may infer a biological transition towards the fibrotic phenotype. This novel approach utilizing platelet transcript analysis may therefore have potential for serially monitoring MPN patients and the early identification of genomic changes that may herald disease transformation to MF.

6 months ago

CCND1 (Cyclin D1) • CEP55 (Centrosomal Protein 55)

MPL W515L

6ms

In Vivo Ablation of NFκB Cascade Effectors Alleviates Disease Burden in Myeloproliferative Neoplasms (ASH 2023)

Through qRT-PCR and mass cytometry, we demonstrate that CA-4948 treatment dampened inflammatory cytokine production induced by IL-1β in primary MPN CD14+ monocytes. Overall, we demonstrate that targeting mediators including Rela, Myd88, and IRAK4 specifically alleviated MPN disease burden without toxicity to healthy tissue and further establish CA-4948 as a promising therapeutic avenue for the treatment of MPN.

6 months ago

Preclinical

JAK2 (Janus kinase 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CHEK2 (Checkpoint kinase 2) • CD34 (CD34 molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • CD14 (CD14 Molecule) • GPX4 (Glutathione Peroxidase 4) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • IL1B (Interleukin 1, beta) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4) • RELA (RELA Proto-Oncogene) • TP53INP1 (Tumor Protein P53 Inducible Nuclear Protein 1)

MPL W515L

emavusertib (CA-4948)

6ms

TGFβ1 Secretion in Megakaryocytes Is Autophagy-Dependent and Its Inhibition Ameliorates Myelofibrosis in Mice (ASH 2023)

In ongoing work, ROCK inhibitors are further being tested in higher doses alone or in combination with the JAK2 inhibitor ruxolitinib. Overall, our data suggest that TGFβ1 secretion is uncoupled from conventional granule secretion in MKs and is instead dependent on RhoA/autophagy signaling pathways. Targeting these pathways in aberrant MKs represents a new potential therapeutic target in the treatment of MF.

6 months ago

Preclinical

RHOA (Ras homolog family member A) • TGFB1 (Transforming Growth Factor Beta 1) • IL1B (Interleukin 1, beta)

MPL W515L

Jakafi (ruxolitinib)

6ms

Zinpentraxin Alfa Reduces Myelofibrosis in a JAK2-V617F Mouse Model of Myeloproliferative Neoplasms (ASH 2023)

ZPN has also been investigated as monotherapy and in combination with ruxolitinib (RUX) in a phase 2 clinical study in patients with myelofibrosis (NCT01981850; Verstovsek S et al, Haematologica 2023). ZPN treatment in a JAK2-V617F mouse model of MPN with myelofibrosis was well tolerated as monotherapy and in combination with RUX. A reduction in the grade of myelofibrosis was observed in all ZPN treatment groups. ZPN showed promising trends in reducing platelet and monocyte counts, while the decrease in hemoglobin by RUX was in part prevented in combination with ZPN.

6 months ago

Preclinical

JAK2 (Janus kinase 2) • CALR (Calreticulin)

JAK2 V617F • MPL W515L

Jakafi (ruxolitinib) • zinpentraxin alfa (RG6354)

6ms

A Rare Case of Essential Thrombocythemia Progressed to Acute Myeloid Leukemia with Concomitant JAK2, CALR, and MPL Mutations (AMP 2023)

Peripheral blood flow cytometry showed 65% myeloblasts, confirming AML, and induction with cytarabine and idarubicin was initiated. MPNs with multiple driver mutations are uncommon, and their clinical behavior and impact on therapy are unclear. In an isolated case series, patients with a double-mutated phenotype tend to be male, have an advanced age of onset, and have lower hemoglobin and higher platelet counts; however, the incidence of thrombosis was not different.

6 months ago

Clinical

TP53 (Tumor protein P53) • JAK2 (Janus kinase 2) • CALR (Calreticulin) • MPL (MPL Proto-Oncogene, Thrombopoietin Receptor)

TP53 mutation • JAK2 V617F • JAK2 mutation • CALR mutation • MPL W515L

cytarabine • idarubicin hydrochloride

6ms

Inhibition of PAK1 generates an ameliorative effect on MPLW515L mouse model of myeloproliferative neoplasms by regulating the differentiation and survival of the megakaryocytes. (PubMed, Exp Hematol)

Notably, PAK1 knockout attenuated the destruction of splenic structure, and reduced the megakaryocyte burden within the BM. These results suggest that the inhibition of PAK1 may be a considerable method treating MPLW515L mutant MPN by intervening megakaryocytes.

6 months ago

Preclinical • Journal

RAC1 (Rac Family Small GTPase 1) • CASP3 (Caspase 3) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)

MPL W515L

12ms

ALGORITM OF MOLECULAR GENETIC EXAMINATION OF PATIENTS WITH PH- NEGATIVE CRONIC MYELOPROLIFERATIVE NEOPLASM (EHA 2023)

Implementation of the proposed study scheme in clinical practice will help improve the diagnosis of patients with suspected MPN Ph-, as well as provide adequate treatment tactics in patients based on their molecular genetic characteristics. Myeloproliferative disorder

12 months ago

Clinical

JAK2 (Janus kinase 2) • CALR (Calreticulin)

JAK2 V617F • JAK2 mutation • MPL W515L

12ms

TARGETING THE SRC HOMOLOGY 2 DOMAIN-CONTAINING PHOSPHATASE SHP2 ENHANCES THE THERAPEUTIC EFFICACY OF JAK INHIBITION IN MYELOPROLIFERATIVE NEOPLASMS (EHA 2023)

Pharmacologic targeting by SHP2 inhibitors TNO155 or IACS-13909 as well as dual SHP2/JAK2 targeting was evaluated in MPN cell lines and primary MPN patient cells. Our findings suggest a relevant role of SHP2 in MPN given enhanced MAPK pathway suppression and correctiveeffects when SHP2 is targeted in MPN cells, mouse models and primary patient isolates. Further studies will delineate the involvement of SHP2 phosphatase vs. non-phosphatase functions and detail the potential of JAK2/SHP2 inhibition as therapeutic approach in MPN.

12 months ago

Clinical

STAT3 (Signal Transducer And Activator Of Transcription 3) • CALR (Calreticulin) • DUSP6 (Dual specificity phosphatase 6) • GAB1 (GRB2 Associated Binding Protein 1)

JAK2 V617F • MPL W515L

Jakafi (ruxolitinib) • batoprotafib (TNO155) • BMS-986466

12ms

Fasudil promotes polyploidization of megakaryoblasts in an acute megakaryocyte leukemia model. (PubMed, Naunyn Schmiedebergs Arch Pharmacol)

Combination therapy of ROCK1 inhibitor fasudil and reported clinical AURKA inhibitor MLN8237 achieved a better antileukemia effect in vivo, which alleviated hepatosplenomegaly and promoted the differentiation of megakaryoblast cells. ROCK1 inhibitor fasudil is a good proliferation inhibitor and polyploidization inducer of megakaryoblast cells and might be a novel rationale for clinical AMKL treatment.

12 months ago

Journal

MPL W515L

alisertib (MLN8237)

almost2years

TGF-β signaling in myeloproliferative neoplasms contributes to myelofibrosis without disrupting the hematopoietic niche. (PubMed, J Clin Invest)

Indeed, treatment with a c-Jun N-terminal kinase (JNK) inhibitor prevents the development of myelofibrosis induced by MPLW515L. Together, these data show that JNK-dependent TGF-β signaling in mesenchymal stromal cells is responsible for the development of myelofibrosis but not hematopoietic niche disruption in MPNs, suggesting that the signals that regulate niche gene expression in bone marrow mesenchymal stromal cells are distinct from those that induce a fibrogenic program.

almost 2 years ago

Journal

SMAD4 (SMAD family member 4) • CXCL12 (C-X-C Motif Chemokine Ligand 12) • TGFB1 (Transforming Growth Factor Beta 1) • MAPK8 (Mitogen-activated protein kinase 8)

CXCL12 expression • MPL W515L

almost2years

CLINICAL AND MOLECULAR CORRELATION OF PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA: A RETROSPECTIVE ANALYSIS FROM A TERTIARY CARE CENTER IN INDIA. (EHA 2022)

Therapy was started in all the patients according to their risk score with hydroxyurea or aspirin as the standard of care. In contrast to western studies, thrombosis was observed to be higher in CALR mutated group than others in our patient population. We recommend larger multicenter study for further elucidation of these observations.

almost 2 years ago

Retrospective data

JAK2 (Janus kinase 2) • CALR (Calreticulin)

JAK2 V617F • JAK2 mutation • CALR mutation • MPL W515L

hydroxyurea

over2years

Genetic Landscape and Clonal Evolution Patterns of CEBPA-Mutated Acute Myeloid Leukaemia Based on Next-Generation Sequencing: A Retrospective Analysis (ASH 2021)

In fact, our data show that the number and the type of concurrent mutation has a prognostic impact, possibly identifying patients eligible to first line allogeneic stem cell transplantation. We identified an allelic variant of SH2B3 that had never been functionally characterized nor associated with AML and that could represent a marker for genetic instability and a potential new target in AML treatment strategies.

over 2 years ago

Retrospective data • Next-generation sequencing

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • NF1 (Neurofibromin 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • WT1 (WT1 Transcription Factor) • BCOR (BCL6 Corepressor) • CSF3R (Colony Stimulating Factor 3 Receptor) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • GATA2 (GATA Binding Protein 2) • CALR (Calreticulin) • SH2B3 (SH2B Adaptor Protein 3)

TP53 mutation • KRAS mutation • NPM1 mutation • DNMT3A mutation • ASXL1 mutation • TET2 mutation • SRSF2 mutation • CEBPA mutation • STAG2 mutation • JAK2 V617F • WT1 mutation • GATA2 mutation • MPL W515L

Oncomine Myeloid Assay GX

over2years

Clinical and Laboratory Features of JAK2 V617F, CALR, and MPL Mutations in Malaysian Patients with Classical Myeloproliferative Neoplasm (MPN). (PubMed, Int J Environ Res Public Health)

JAK2V617F and CALR mutations play an important role in diagnostics. Hence, every patient suspected of having a myeloproliferative neoplasm should be screened for these mutations.

over 2 years ago

Clinical • Journal

JAK2 (Janus kinase 2) • CALR (Calreticulin)

JAK2 V617F • CALR mutation • MPL W515L

almost3years

TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors. (PubMed, Cancer Res)

Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically.

almost 3 years ago

Journal • BRCA Biomarker • PARP Biomarker

ABL1 (ABL proto-oncogene 1) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • BCR (BCR Activator Of RhoGEF And GTPase) • DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • WT1 (WT1 Transcription Factor) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)

FLT3-ITD mutation • DNMT3A mutation • TET2 mutation • NRAS G12 • JAK2 V617F • WT1 mutation • MPL W515L

almost3years

Low JAK2 V617F Allele Burden in Ph-Negative Chronic Myeloproliferative Neoplasms Is Associated with Additional CALR or MPL Gene Mutations. (PubMed, Genes (Basel))

Therefore, in cases of detecting MPNs with a low allelic load JAK2 V617F, it may be advisable to search for other molecular markers, primarily mutations in exon 9 of CALR. The load of the combined mutations measured at different time points may indicate that, at least in some cases, these mutations could be represented by different clones of malignant cells.

almost 3 years ago

Journal

JAK2 (Janus kinase 2) • CALR (Calreticulin)

JAK2 V617F • JAK2 mutation • CALR mutation • MPL W515L

over3years

[VIRTUAL] CREB3L1 Overexpression Can Reliably Discriminate Ph-MPNs from Reactive Cases (ASH 2020)

We demonstrate that CREB3L1 overexpression can single-handedly and reliably discriminate Ph-MPNs from reactive hypercytosis, reactive myelofibrosis, and CML. Early utilization of this method in the diagnostic process can guide patients to an efficient diagnosis and free many patients from unnecessary testing.

over 3 years ago

Clinical

JAK2 (Janus kinase 2)

JAK2 V617F • MPL W515L

over3years

[VIRTUAL] TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors (ASH 2020)

Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Our findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically.

over 3 years ago

BRCA Biomarker • PARP Biomarker

ABL1 (ABL proto-oncogene 1) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • WT1 (WT1 Transcription Factor) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)

BRCA1 mutation • FLT3-ITD mutation • DNMT3A mutation • TET2 mutation • NRAS G12 • BRCA1 mutation + BRCA2 mutation • JAK2 V617F • WT1 mutation • MPL W515L