Myeloproliferative Research Articles

TP53 Mutations in Myeloproliferative Neoplasms: Context-Dependent Evaluation of Prognostic Relevance.

The clinical relevance of TP53 mutations (TP53MUT) in myeloproliferative neoplasms (MPN) and their prognostic interaction with MPN subtype designation has not been systematically studied. In the current study, 114 patients with MPN harboring TP53MUT (VAF ≥ 2%) were evaluated for overall survival (OS), calculated from the time of TP53MUT detection: chronic phase myelofibrosis (MF-CP; N = 61); blast-phase (MPN-BP; N = 31) or accelerated-phase (MPN-AP; N = 16) MPN, and polycythemia vera/essential thrombocythemia (PV/ET; N = 6). Sixty-five (57%) patients harbored International Consensus Classification (ICC)-defined multihit TP53MUT and 56 (49%) monosomal/complex karyotype (MK/CK). Majority of MPN-BP (90%) and MPN-AP (81%) while 39% of MF-CP and none of PV/ET patients harbored multihit TP53MUT. OS in MPN-BP and MPN-AP was equally dismal (median 6 vs. 4.5 months, respectively; p = 1.0), regardless of multihit configuration (p = 0.44), while OS in TP53MUT MPN-BP/AP (N = 47; median 4 months) was inferior to that of a separate cohort (N = 49) with TP53 wild-type MPN-BP/AP (median 11 months; p < 0.01). OS in MF-CP was significantly shorter with multihit versus non-multihit TP53MUT (median 10 vs. 35 months; HR 2.9; p < 0.01), independent of other MF-relevant genetic risk factors, including ASXL1/SRSF2/U2AF1 mutations. Multihit TP53MUT was also associated with inferior survival following allogeneic stem cell transplant (ASCT): median 9 months versus "not reached" in patients with (N = 9) versus without (N = 8) multihit TP53MUT (p < 0.01). The presence of multihit or non-multihit TP53MUT in MPN-BP/AP or multihit TP53MUT in MF-CP is associated with exceptionally poor prognosis and justifies inclusion into the ICC category of "myeloid neoplasms with mutated TP53." By contrast, detection of non-multihit TP53MUT, by itself, might not endanger short-term survival in MF-CP, PV, or ET.

Deciphering the complex clonal heterogeneity of polycythemia vera and the response to interferon alpha.

Interferon alpha (IFNa) is approved for the therapy of patients (pts) with polycythemia vera (PV), a subtype of myeloproliferative neoplasms (MPN). Some pts achieve molecular responses (MR), but clonal factors sensitizing for MR remain elusive. We integrated colony formation and differentiation assays with single-cell RNA seq and genotyping in PV-derived cells vs. healthy controls (HC) to dissect how IFNa targets diseased clones during erythroid differentiation. IFNa significantly decreased colony growth in MPN and HC, with variable transcriptional responses observed in individual colonies. scRNAseq of colonies demonstrated more mature erythroid PV-derived colonies compared with HC. JAK2V617F-mutant cells exhibited upregulated STAT5A, heme, and G2M checkpoint pathways compared to JAK2WT cells from the same pts. Subgroup analysis revealed that IFNa significantly decreased immature erythrocytic cells in PV (basophilic erythroblasts p<0.05; polychromatic erythroblasts p<0.05) but not in HC. CD71-/CD235a+ cells from HC (p<0.05) but not from PV pts were inhibited by IFNa, and number of reticulocytes was less affected in PV. Robust IFNa responses persisted throughout differentiation, leading to significant apoptosis in PV. Apoptotic cells displayed downregulation of ribosomal genes. This link between apoptosis and ribosomal genes was corroborated through analysis of mitochondrial variants demonstrating IFNa-induced eradication of specific clones, characterized by elevated expression of ribosomal genes. Our findings indicate that PV-derived clones either undergo apoptosis or pass through differentiation, overall reducing cycling mutant cells over long-term treatment. Further, the significance of ribosomal genes and clonal prerequisites in IFNa's therapeutic mechanism is underscored, shedding light on the intricate dynamics of IFNa treatment in PV.

Essential Thrombocythemia: A Review.

Essential thrombocythemia, a clonal myeloproliferative neoplasm with excessive platelet production, is associated with an increased risk of thrombosis and bleeding. The annual incidence rate of essential thrombocythemia in the US is 1.5/100 000 persons. Patients with essential thrombocythemia have a persistent platelet count of 450 × 109/L or greater. The differential diagnosis includes myeloproliferative neoplasms (polycythemia vera, primary myelofibrosis, chronic myeloid leukemia); inflammatory conditions such as rheumatoid arthritis and systemic lupus erythematosus; infections; splenectomy; iron deficiency anemia; and solid tumors such as lung cancer. Approximately 90% of individuals with essential thrombocythemia have genetic variants that upregulate the JAK-STAT (signal transducer and activator of transcription 5) signaling pathway, including Janus kinase 2 (JAK2, 64%), calreticulin (CALR, 23%), and myeloproliferative leukemia virus oncogene (MPL, 4%). The median age at diagnosis of essential thrombocythemia is 59 years. The median overall survival exceeds 35 years in those diagnosed at 40 years or younger. Patients with essential thrombocythemia are at increased risk of arterial thrombosis (11%), venous thrombosis (7%), and hemorrhagic complications (8%). Thrombosis risk is increased among those with a history of thrombosis, age older than 60 years, a JAK2 gene variant, and cardiovascular risk factors (eg, hypertension, diabetes mellitus, hyperlipidemias, tobacco use). Use of aspirin (81-100 mg/d) is suggested for most patients with essential thrombocythemia to lower thrombosis risk. In a retrospective study of 300 affected patients with a low thrombosis risk (younger than 60 years with no prior thrombosis), those not taking aspirin (100 mg/d) had a risk of arterial thrombosis of 9.4/1000 patient-years and a venous thrombosis risk of 8.2/1000 patient years; cardiovascular risk factors were associated with a higher risk of arterial thrombi (incidence rate ratio, 2.5 [95% CI, 1.02-6.1]), and a JAK2 gene variant was associated with increased risk of venous thrombosis (incidence rate ratio, 4.0 [95% CI, 1.2-12.9]). In a randomized trial of 114 patients at higher risk for thrombosis (age older than 60 years or a prior thrombotic event), cytoreduction with hydroxyurea significantly lowered the risk of arterial or venous thrombotic events compared with no cytoreductive therapy (3.6% vs 24%; P < .01). At a median of 8.5 years from diagnosis, approximately 10% of patients with essential thrombocythemia develop myelofibrosis and about 3% develop acute myeloid leukemia. Essential thrombocythemia is a rare clonal myeloproliferative neoplasm associated with an increased risk of venous and arterial thrombosis, hemorrhage, myelofibrosis, and acute myeloid leukemia. Based on individual risk factors for thrombosis, persons with essential thrombocythemia may be treated with low-dose aspirin, either alone or in combination with a cytoreductive drug such as hydroxyurea.

Folate metabolism in myelofibrosis: a missing key?

Folates serve as key enzyme cofactors in several biological processes. Folic acid supplementation is a cornerstone practice but may have a "dark side". Indeed, the accumulation of circulating unmetabolized folic acid (UMFA) has been associated with various chronic inflammatory conditions, including cancer. Additionally, by engaging specific folate receptors, folates can directly stimulate cancer cells and modulate the expression of genes coding for pro-inflammatory and pro-fibrotic cytokines.This evidence could be extremely relevant for myelofibrosis (MF), a chronic myeloproliferative neoplasm typified by the unique combination of clonal proliferation, chronic inflammation, and progressive bone marrow fibrosis. Folate supplementation is frequently associated with conventional or investigational drugs in the treatment of MF-related anemia to tackle ineffective erythropoiesis. In this review, we cover the different aspects of folate metabolism entailed in the behavior and function of normal and malignant hematopoietic cells and discuss the potential implications on the biology of myelofibrosis.

Arginine vasopressin deficiency associated with accelerated phase myeloproliferative neoplasm with monosomy 7

Arginine vasopressin deficiency associated with accelerated phase myeloproliferative neoplasm with monosomy 7

Effect of ten-eleven translocation methylcytosine dioxygenase 2 gene mutations on the secondary myelofibrosis of JAK2V617F positive myeloproliferative neoplasms patients

Objective: To investigate the effect of ten-eleven translocation methylcytosine dioxygenase 2 (TET2) gene mutations on the secondary myelofibrosis (SMF) of JAK2V617F+ myeloproliferative neoplasms (MPN) patients. Method: A retrospective collection was conducted on MPN patients with JAK2V617F mutation detected by second-generation sequencing in the Department of Hematology, the Second Hospital of Tianjin Medical University. TET2+JAK2V617F+ MPN patients were selected as the mutant group, and TET2-JAK2V617F+ MPN patients matched for age and gender were selected as the non-mutant group. The differences in mortality and SMF between the two groups were followed up until November 11, 2022. The second-generation sequencing technology was used to detect 325 mutated genes in hematological malignancies, in order to determine the differences between two groups of mutated genes. Enzyme linked immunosorbent assay (ELISA) was used to detect and compare the levels of cytokines such as transforming growth factor (TGF)-β1, interleukin (IL)-17, interferon (IFN)-γ in the bone marrow supernatant of the both groups. Multivariate Cox regression analysis was used to investigate the influencing factors of SMF in JAK2V617F+ MPN patients. Result: A total of 96 patients were included, with 32 in the mutant group, including 16 males and 16 females, aged [M (Q1, Q3)] 61 (53, 70) years, and 64 in the non-mutant group, including 32 males and 32 females, aged 58 (51, 68) years. After a follow-up of 61(43, 116) months, the mortality rate of patients in the mutant group [15.6% (5/32) vs 1.6% (1/64), P=0.007] and the proportion of SMF [43.8% (14/32) vs 14.1% (9/64), P=0.001] were higher than those in the non-mutant group. The proportion of FAT1 [25.0% (8/32) vs 7.8% (5/64), P=0.028], U2AF1 [15.6% (5/32) vs 0, P=0.003], and KMT2D [15.6% (5/32) vs 3.1% (2/64), P=0.039] gene mutations in the mutant group was higher than that in the non-mutant group. The mutant group had higher levels of TGF-β1 [13 837(8 298, 17 509) vs 7 915 (3 586, 10 545) ng/L, P=0.016], IL-17 [7.4 (6.3, 7.5) vs 6.1 (5.9, 7.1) ng/L, P=0.007], and IFN-γ[8.5 (8.1, 9.1) vs 8.0 (7.5, 8.3) ng/L, P=0.007] compared to the non-mutant group. The results of multivariate Cox regression analysis showed that TET2 mutation (HR=8.483, 95%CI: 1.278-56.330) was a risk factor of SMF in JAK2V617F+ MPN patients. Conclusion: TET2 mutation is a risk factor for SMF in JAK2V617F+ MPN patients.

Spleen volume assessment in Ph-negative chronic myeloproliferative neoplasms: a real-life study comparing ultrasonography vs. magnetic resonance imaging scans.

Splenomegaly is a quite common clinical feature of Philadelphia (Ph) negative chronic myeloproliferative neoplasms (MPNs) and its presence may, in some cases, drives treatment decision. Most importantly, palpable splenomegaly is a minor criterion for both pre-fibrotic/early primary myelofibrosis and primary myelofibrosis (PMF) diagnosis, even if clinical assessment by physical examination is poorly reliable and accurate. On the other hand, despite the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet guidelines defined spleen response criteria by palpation, they also recognized the highly subjective nature of spleen size assessment by physical examination, and recommended objective confirmation of volume reduction via computed tomography or magnetic resonance imaging (MRI). In particular, spleen volume (SV) reduction of at least 35% via MRI is typically the primary endpoint in PMF and in some polycythemia vera clinical trials. Nevertheless, this technique seems inconvenient in routine clinical practice. To simplify serial monitoring of spleen size by using ultrasonography (US), we retrospectively analyzed medical records of 39 newly diagnosed MPN patients who underwent spleen ultrasonography as well as MRI. The median SV assessed by US was 600ml (range 200-5000ml) while median SV evaluated by MRI was 553.1ml (range 172-5140ml), revealing a strong linear relationship between methods, with a correlation coefficient of r = 0.96 (95% CI 0.92-0.98, P < 0.0001). Our findings support the role of US into pre-screening assessments for clinical trials and practice, offering a pragmatic solution for evaluating SV in MPN patients and ultimately improving patient care and clinical decision-making in this complex disease landscape.

Calreticulin-From the Endoplasmic Reticulum to the Plasma Membrane-Adventures of a Wandering Protein.

Calreticulin (CRT) is a 46 kDa highly conserved protein initially identified as calregulin, a prominent Ca2+-binding protein of the endoplasmic reticulum (ER). Subsequent studies have established that CRT functions in the ER's protein folding response and Ca2+ homeostatic mechanisms. An ER retention signal on the carboxyl terminus of CRT suggested that CRT was restricted to the ER. However, the identification of CRT in the nucleus and cytosol has established that CRT is a multi-compartmental, multifunctional protein. CRT also plays an important role in cancer progression. Most recently, CRT was identified on the cell surface and shown to be a potent 'eat-me' signal that plays a key role in the uptake of apoptotic and viable cancer cells by phagocytes. Elevated CRT exposure on the outer leaflet of cancer cells has been linked with anticancer immunity and superior therapeutic outcomes in patients with non-small cell lung carcinoma, colorectal carcinoma, acute myeloid leukemia, ovarian cancer, and high-grade serous carcinomas. Mutations in the CRT gene have been identified in a subset of patients with myeloproliferative neoplasms. The most recent studies from our laboratory have revealed a new and significant function for extracellular CRT as a plasminogen receptor. This discovery has profound implications for our understanding of the role of CRT in myeloproliferative neoplasms, specifically, essential thrombocythemia.

RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia

Myeloid malignancies are heterogenous disorders characterized by distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. Here, we establish a comprehensive transcriptional atlas across the spectrum of myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML) through RNA-sequencing of 158 primary samples encompassing CD34+ hematopoietic stem/progenitor cells and CD14+ monocytes. Supported by mass cytometry (CyTOF) profiling, we reveal aberrant networks of PI3K/AKT/mTOR signalling and NFκB-mediated hyper-inflammation. Combining ATAC-Seq, CUT&Tag, RNA-seq, and CyTOF, we demonstrate that targeting of ribosomal protein S6 kinase A1 (RSK1) suppresses NFκB activation and diminishes pro-inflammatory mediators including tumor necrosis factor (TNF) associated with MPN disease severity and transformation. We further evaluate a therapeutic approach utilizing a first-in-class RSK inhibitor, PMD-026, currently in Phase 2 development for breast cancer, for use in myeloid malignancies. Treatment with PMD-026 suppressed disease burden across seven syngeneic and patient-derived xenograft leukemia mouse models spanning the spectrum of driver and disease-modifying mutations. These findings uncover a therapeutic avenue for a conserved dependency across MPN and sAML.

CML- A IMPOSTER WITH MANY FACES

Objective: The classification of chronic myeloproliferative diseases by the World Health Organisation includes eight forms of bone marrow neoplasms, including polycythaemia vera and Breakpoint cluster region-ABL viral oncogene homolog 1(BCR-ABL)-positive CML. Polycythaemia vera is diagnosed in the majority of cases (95%) only when the Janus kinase-2 mutation is present and the Breakpoint cluster region-Abelson murine (BCR-ABL) leukaemia viral oncogene homolog-1 rearrangement is negative. Methods: Methods are not explicitly stated in the abstract; however, the study seems to have involved genetic testing and diagnostic evaluation to identify specific mutations and rearrangements associated with the conditions. Results: With no Janus kinase-2 mutation, the presence of the Philadelphia chromosome, and the BCR-ABL leukaemia viral oncogene homolog one fusion gene, we report a case with erythrocytosis as the main feature of chronic myeloid leukaemia. Conclusion: The case highlights a rare occurrence in the diagnosis of chronic myeloid leukaemia where typical genetic markers of polycythaemia vera are absent, indicating the complexity and variability in the genetic landscape of myeloproliferative diseases.

Endothelial Damage in JAK2V617F Myeloproliferative Neoplasms with Splanchnic Vein Thrombosis.

JAK2V617F-mutated myeloproliferative neoplasms (MPN) exhibit abnormal proliferation of bone marrow progenitors and increased risk of thrombosis, specifically in splanchnic veins (SVT). The contribution of the endothelium to the development of the prothrombotic phenotype was explored. Plasma and serum samples from JAK2V617F MPN patients with (n=26) or without (n=7) thrombotic debut and different treatments, were obtained (n=33). Cultured endothelial cells (ECs) were exposed to serum samples from these patients and from healthy donors as controls. Changes in markers of inflammation (VCAM-1, ICAM-1), cell permeability (VE-cadherin), production of VWF, extracellular matrix (ECM) reactivity, and activation of intracellular signaling pathways related to stress, proliferation, inflammation (Akt, p44/42, IkBa), and JAK2/STAT3 pathway, were assessed by immunofluorescence, flow adhesion, SDS-PAGE and immunoblot. Additionally, circulating markers of endothelial activation and damage (VWF, sVCAM-1, sTNFRI, thrombomodulin, angiopoietin-2, a2-antiplasmin activity, PAI-1) were evaluated in Patients' plasma. The in vitro studies showed that EC exposure to MPN thrombotic patients' sera resulted in increased VCAM-1 and ICAM-1, and reduced VE-cadherin expression (p<0.05) at the cell surface. Production and release of VWF to the ECM were higher (p<0.05), with increased platelet adhesion after perfusing whole blood, being more noticeable in response to sera from non-treated patients. Furthermore, intracellular activation of Akt, p44/42, IkBa and JAK2/STAT3 was observed. Moreover, plasma levels of VWF, TNF-R1, VCAM-1, thrombomodulin, and angiopoietin-2 were higher in JAK2V617F+ MPN patients with thrombosis. The present findings suggest that circulating factors in MPNs with SVT debut induce endothelial proinflammatory and prothrombotic phenotypes, which are modulated in vitro with MPN treatment.

Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis

BackgroundClonal myeloproliferation and fibrotic transformation of the bone marrow (BM) are the pathogenetic events most commonly occurring in myelofibrosis (MF). There is great evidence indicating that tumor microenvironment is characterized by high lactate levels, acting not only as an energetic source, but also as a signaling molecule.MethodsTo test the involvement of lactate in MF milieu transformation, we measured its levels in MF patients’ sera, eventually finding a massive accumulation of this metabolite, which we showed to promote the expansion of immunosuppressive subsets. Therefore, to assess the significance of its trafficking, we inhibited monocarboxylate transporter 1 (MCT1) by its selective antagonist, AZD3965, eventually finding a mitigation of lactate-mediated immunosuppressive subsets expansion. To further dig into the impact of lactate in tumor microenvironment, we evaluated the effect of this metabolite on mesenchymal stromal cells (MSCs) reprogramming.ResultsOur results show an activation of a cancer-associated phenotype (CAF) related to mineralized matrix formation and early fibrosis development. Strikingly, MF serum, enriched in lactate, causes a strong deposition of collagen in healthy stromal cells, which was restrained by AZD3965. To corroborate these outcomes, we therefore generated for the first time a TPOhigh zebrafish model for the establishment of experimental fibrosis. By adopting this model, we were able to unveil a remarkable increase in lactate concentration and monocarboxylate transporter 1 (MCT1) expression in the site of hematopoiesis, associated with a strong downregulation of lactate export channel MCT4. Notably, exploiting MCTs expression in biopsy specimens from patients with myeloproliferative neoplasms, we found a loss of MCT4 expression in PMF, corroborating changes in MCT expression during BM fibrosis establishment.ConclusionsIn conclusion, our results unveil lactate as a key regulator of immune escape and BM fibrotic transformation in MF patients, suggesting MCT1 blocking as a novel antifibrotic strategy.

A decade-long analysis of 98 chronic myeloid leukemia patients: Laboratory data and clinical progress at a single center

Abstract: BACKGROUND: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome (BCR-ABL1 fusion gene). CML primarily progresses through chronic, accelerated, and blast phases. While global studies on BCR-ABL1 fusion transcript types and their associations with clinical, laboratory, and prognostic profiles exist, such data is scarce in Malaysia. OBJECTIVES: This study aimed to determine the distribution of BCR-ABL1 fusion transcript types and evaluate their associations with demographic, clinical, laboratory, prognostic profiles, and disease outcomes among Malaysian CML patients. PATIENTS, MATERIALS AND METHODS: A total of 98 patients diagnosed with CML were identified at East Coast Hospital, Malaysia. This 12-year cross-sectional study was carried out using data extracted from patients’ medical records. Molecular results for BCR-ABL1 fusion genes were obtained using one-step multiplex reverse transcriptase polymerase chain reaction. RESULTS: Out of the 98 patients, 56% had e14a2, 41% had e13a2 fusion transcripts, while the remaining 2 patients had e14a3 transcripts. Additionally, 1 patient co-expressed both e13a2 and e14a2. Among patients with the major BCR-ABL1 transcript type, those with e14a2 fusion transcripts showed an older median age (P = 0.025), while patients with e13a2 fusion transcripts had significantly higher white blood cell (WBC) counts (P = 0.014). Furthermore, there were significantly more patients with blastic transformation in the e13a2 group (P = 0.038). The median latency period of CML was 12 months. The blast cell lineages consisted of myeloid (68.4%), followed by B-lymphoid (26.3%) and mixed phenotypic (5.3%). The differences in fusion transcript expression might influence certain parameters; for instance, older patients were associated with the e14a2 fusion transcript. Meanwhile, patients exhibiting e13a2 might have a higher WBC count at diagnosis and be more vulnerable to blastic transformation of CML. CONCLUSIONS: This study highlights the predominance of e14a2 fusion transcripts in Malaysian CML patients and its association with older age. The e13a2 transcript was linked to higher tumor burden and a higher rate of blastic transformation, suggesting potential prognostic significance. These findings underscore the importance of baseline molecular profiling for optimizing disease management.

Chronic Neutrophilic Leukemia: Advances in Diagnosis, Genetic Insights, and Management Strategies.

CNL is a rare subtype of MPNs characterized by persistent neutrophilia, bone marrow hypercellularity, and specific genetic mutations, particularly in the CSF3R gene. Advances in molecular diagnostics have greatly enhanced our understanding of CNL, distinguishing it from other myeloproliferative disorders and refining diagnostic criteria. This review provides an updated overview of CNL, focusing on breakthroughs in genetic profiling, including novel mutations with potential prognostic value and implications for targeted therapy. We discuss current management strategies, emphasizing the role of JAK inhibitors, allogeneic stem cell transplantation, and evolving investigational treatments. Challenges in early diagnosis, therapeutic resistance, and future directions in research are also addressed, underscoring the need for a personalized medicine approach to improve outcomes for patients with CNL.

Mutant Calreticulin in MPN: Mechanistic Insights and Therapeutic Implications.

More than a decade following the discovery of Calreticulin (CALR) mutations as drivers of myeloproliferative neoplasms (MPN), advances in the understanding of CALR-mutant MPN continue to emerge. Here, we summarize recent advances in mehanistic understanding and in targeted therapies for CALR-mutant MPN. Structural insights revealed that the mutant CALR-MPL complex is a tetramer and the mutant CALR C-terminus is exposed on the cell surface. Targeting mutant CALR utilizing antibodies is the leading therapeutic approach, while mutant CALR-directed vaccines are also in early clinical trials. Additionally, chimeric antigen receptor (CAR) T-cells directed against mutant CALR are under evaluation in preclinical models. Approaches addressing the cellular effects of mutant CALR beyond MPL-JAK-STAT activation, such as targeting the unfolded protein response, proteasome, and N-glycosylation pathways, have been tested in preclinical models. In CALR-mutant MPN, the path from discovery to mechanistic understanding to direct therapeutic targeting has advanced rapidly. The longer-term goal remains clonally-selective therapies that modify the disease course in patients.

A case of myeloproliferative neoplasm with eosinophilia associated with PCM1-JAK2 rearrangement

A case of myeloproliferative neoplasm with eosinophilia associated with PCM1-JAK2 rearrangement

Dual ASXL1 and CSF3R mutations drive myeloid biased stem cell expansion and enhance neutrophil differentiation.

Mutations in the epigenetic regulator Additional Sex Combs-Like 1 (ASXL1) are frequently observed in chronic neutrophilic leukemia (CNL). CNL is a myeloproliferative neoplasm (MPN) driven by activating mutations in the Colony Stimulating Factor 3 Receptor (CSF3R), which cause excessive neutrophil production. Despite the high rates of co-occurrence, the interplay between ASXL1 and CSF3R mutations in hematopoiesis and leukemia remains poorly understood. Here, we present a new mouse model with both Asxl1Y588X and Csf3rT621I mutations, which recapitulates features of human MPNs. Csf3r-mutant mice exhibit an age-associated depletion of hematopoietic stem cells, which is tempered by adding of Asxl1Y588X. This combination of mutations causes an expansion of myeloid-biased long-term hematopoietic stem cells. As the mice age, they develop neutrophilia, but leukemia is rare, suggesting additional mutations may be required for transformation. Using models of myeloid differentiation, we find that Asxl1 truncation enhances CSF3RT618I-driven neutrophil differentiation, activating inflammatory pathways associated with mature myeloid cell production. Moreover, cells with both mutations have increased H3K4me1 at neutrophil-associated enhancers. Mutant ASXL1 is known to decrease the genome-wide abundance of the repressive histone mark H2AK119ub. While we see the expected decrease in H2AK119ub in Asxl1-mutant cells, this effect is reversed when CSF3R is also mutated, suggesting a complex interplay between these mutations in regulating chromatin dynamics during hematopoiesis. Our findings highlight context-dependent effects of ASXL1 mutation in myeloid disorders and provide insights into the mechanisms underlying neutrophil differentiation in ASXL1 and CSF3R dual mutant MPN.

Impact of Recent Translational and Therapeutic Developments on Clinical Course of BCR::ABL1-Positive and -Negative Myeloproliferative Neoplasms.

Despite the study of BCR::ABL1-positive and -negative myeloproliferative neoplasms (MPNs) providing seminal insights into cancer biology, tumor evolution and precision oncology over the past half century, significant challenges remain. MPNs are clonal hematopoietic stem cell-derived neoplasms with heterogenous clinical phenotypes and a clonal architecture which impacts the often-complex underlying genetics and microenvironment. The major driving molecular abnormalities have been well characterized, but debate on their role as disease-initiating molecular lesions continues. The introduction of the ABL1 tyrosine kinase inhibitors have been extremely successful in the treatment of chronic myeloid leukemia with most patients having a near-normal life expectancy. Similar success has, however, not been achieved for BCR::ABL1-negative MPNs in terms of disease course modification and most patients remain incurable. In both disease categories, genomic instability seems to increase the risk of disease progression to accelerated/blast phase, which is resistant/refractory to conventional treatment and associated with a poor prognosis. To address some of these issues, the late John Goldman and Tariq Mughal founded a scientific and clinical platform in 2006, the Post-American Society of Hematology (ASH) MPN workshop, to appraise novel cancer biology, candidate therapeutic targets, treatments and other clinical challenges and pay tribute to all the many scientists and clinicians around the world instrumental to the progress made and continuing advances being made. This paper summarizes some of the recent data discussed at the 18th edition of the workshop and includes reference to some data presented or published after the workshop, including the 26th John Goldman CML conference.

Cardiovascular Risk Factors in Myeloproliferative Neoplasms: Associations with Survival and Thrombotic Outcomes

Cardiovascular Risk Factors in Myeloproliferative Neoplasms: Associations with Survival and Thrombotic Outcomes

Single nucleotide polymorphism and promoter methylation analysis of protein tyrosine phosphatase 1B in patients with myeloproliferative neoplasms

Single nucleotide polymorphism and promoter methylation analysis of protein tyrosine phosphatase 1B in patients with myeloproliferative neoplasms