scholarly journals NPM1-Mutated Myeloid Neoplasms with <20% Blasts: A Really Distinct Clinico-Pathologic Entity?

2020 ◽  
Vol 21 (23) ◽  
pp. 8975
Author(s):  
Fabio Forghieri ◽  
Vincenzo Nasillo ◽  
Ambra Paolini ◽  
Francesca Bettelli ◽  
Valeria Pioli ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Myeloproliferative Neoplasm ◽  
Gene Mutations ◽  
Moderate Intensity ◽  
Rapid Progression ◽  
Myeloid Neoplasms ◽  
Blast Count ◽  
Aggressive Clinical Course ◽  
Myelomonocytic Leukemia ◽  
Acute Myeloid

Nucleophosmin (NPM1) gene mutations rarely occur in non-acute myeloid neoplasms (MNs) with <20% blasts. Among nearly 10,000 patients investigated so far, molecular analyses documented NPM1 mutations in around 2% of myelodysplastic syndrome (MDS) cases, mainly belonging to MDS with excess of blasts, and 3% of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) cases, prevalently classified as chronic myelomonocytic leukemia. These uncommon malignancies are associated with an aggressive clinical course, relatively rapid progression to overt acute myeloid leukemia (AML) and poor survival outcomes, raising controversies on their classification as distinct clinico-pathologic entities. Furthermore, fit patients with NPM1-mutated MNs with <20% blasts could benefit most from upfront intensive chemotherapy for AML rather than from moderate intensity MDS-directed therapies, although no firm conclusion can currently be drawn on best therapeutic approaches, due to the limited available data, obtained from small and mainly retrospective series. Caution is also suggested in definitely diagnosing NPM1-mutated MNs with blast count <20%, since NPM1-mutated AML cases frequently present dysplastic features and multilineage bone marrow cells showing abnormal cytoplasmic NPM1 protein delocalization by immunohistochemical staining, therefore belonging to NPM1-mutated clone regardless of blast morphology. Further prospective studies are warranted to definitely assess whether NPM1 mutations may become sufficient to diagnose AML, irrespective of blast percentage.

scholarly journals The Role of Nucleophosmin 1 (NPM1) Mutation in the Diagnosis and Management of Myeloid Neoplasms

Life ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 109
Author(s):  
Katalin Kelemen
Keyword(s):  
Human Cancer ◽  
Rapid Progression ◽  
Npm1 Mutation ◽  
Multifunctional Protein ◽  
Myeloid Neoplasm ◽  
Myeloid Neoplasms ◽  
Blast Count ◽  
Aggressive Clinical Course

Nucleophosmin (NPM1) is a multifunctional protein with both proliferative and growth-suppressive roles in the cell. In humans, NPM1 is involved in tumorigenesis via chromosomal translocations, deletions, or mutation. Acute myeloid leukemia (AML) with mutated NPM1, a distinct diagnostic entity by the current WHO Classification of myeloid neoplasm, represents the most common diagnostic subtype in AML and is associated with a favorable prognosis. The persistence of NPM1 mutation in AML at relapse makes this mutation an ideal target for minimal measurable disease (MRD) detection. The clinical implication of this is far-reaching because NPM1-mutated AML is currently classified as being of standard risk, with the best treatment strategy (transplantation versus chemotherapy) yet undefined. Myeloid neoplasms with NPM1 mutations and <20% blasts are characterized by an aggressive clinical course and a rapid progression to AML. The pathological classification of these cases remains controversial. Future studies will determine whether NPM1 gene mutation may be sufficient for diagnosing NPM1-mutated AML independent of the blast count. This review aims to summarize the role of NPM1 in normal cells and in human cancer and discusses its current role in clinical management of AML and related myeloid neoplasms.

SRSF2 is Mutated in 47.2% (77/163) of Chronic Myelomonocytic Leukemia (CMML) and Prognostically Favorable in Cases with Concomitant RUNX1 mutations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 274-274 ◽  
Author(s):  
Susanne Schnittger ◽  
Manja Meggendorfer ◽  
Alexander Kohlmann ◽  
Vera Grossmann ◽  
Kenichi Yoshida ◽  
...  
Keyword(s):  
Hot Spot ◽  
Myeloproliferative Neoplasm ◽  
Gene Mutations ◽  
Chronic Myelomonocytic Leukemia ◽  
Structural Basis ◽  
Employment Equity ◽  
Cell Counts ◽  
Number Of Genes ◽  
Equity Ownership ◽  
Myelomonocytic Leukemia

Abstract Abstract 274 Introduction: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy characterized by features of both a myeloproliferative neoplasm and a myelodysplastic syndrome. We previously investigated 81 CMML cases and detected a number of genes frequently mutated (TET2 44.4%, CBL 22.2%, NRAS 22.2%, KRAS 12.3%, JAK2 9.8%, RUNX1 8.7%, EZH2 12.3% (Kohlmann et al., JCO, 2010; Grossmann et al., Leukemia, 2011). Recently, we detected a new candidate gene, SRSF2 (serine/arginine-rich splicing factor 2, also known as SC35) that is a component of the RNA splicing machinery and found it to be frequently mutated in MDS. Aim: As CMML has been increasingly characterized by a growing number of genes during the last years we here analyzed both the frequency of SRSF2 mutations in this entity and the relevance in the context of other previously described gene mutations, as well as to look for a potential prognostic implication. Patients and Methods: In total, 163 cases with CMML (CMML-1 n=105, CMML-2 n=58) were included. The cohort comprised 115 males and 48 females with a median age of 72.8 yrs (range: 21.9 – 88.8 yrs) including all 81 pts that have been published previously. 112 cases (69%) had a normal karyotype and 51 (31%) showed aberrant karyotypes. The mutational hot spot region of SRSF2 around Proline codon 95 (P95) was analyzed by Sanger sequencing in all cases. Data on further mutations were available in respective subcohorts: ASXL1 (n=128), CBL (n=162), EZH2 (n=134), JAK2V617F (n=162), KRAS (n=140), NRAS (n=79), RUNX1 (n=156), TET2 (n=143), TP53 (n=80). Results:SRSF2 mutations of P95 were detected in 77/163 (47.2%) of all cases (49/105, 46.7% in CMML-1, and 28/58, 48.3% in CMML-2). In detail, 74 cases had a missense mutation leading to a change of P95 to P95H (n=33), P95L (n=24), P95R (n=16) or P95A (n=1). In further 3 cases a newly described 24 bp (8 amino acids) deletion starting at P95 was observed. All cases had a mutation load of approximately 50%. The mutations were correlated with higher age (73.3 yrs vs 68.7 yrs in the SRSF2wt cases, p=0.010) and higher hemoglobin levels (11.4 vs 10.5 g/dl in the SRSF2wt cases, p=0.019) whereas white blood cell counts were not different. Further, SRSF2 mutations were mutually exclusive of EZH2 mutations (0/12, 0% vs. 66/122, 54.1% in the EZH2wt, p<0.001) whereas a high coincidence occurred with RUNX1 mutations (22/35, 62.9% vs 52/121, 43% in the RUNX1wt, p=0.054) and TET2 mutations (50/82, 61% vs 18/61, 29.5% in the TET2wt, p<0.001). With respect to associations with all other gene mutations investigated and karyotype no specific pattern was observed. In the total cohort no impact of SRSF2 on survival was observed. Because of the high coincidence of SRSF2mut with RUNX1mut and TET2mut, we performed an analysis in these specific subcohorts. No impact of SRSF2mut in the TET2mut subcohort was found. Whereas in the RUNX1mut subcohort SRSF2mut had a favorable impact on overall survival compared to SRSF2wt (median OS: 108.0 months vs 41.8 months, p=0.05). Conclusions:SRSF2 has recently been described as a new marker in CMML and demonstrated to be useful to delineate further the genetic defects of this disease. This very frequent new mutation is characterized by higher age, higher hemoglobin levels and a high coincidence with TET2 and RUNX1 mutations. It is mutually exclusive of EZH2 mutations. In the subset of RUNX1 mutated CMML SRSF2 mutations demonstrated a favorable impact on outcome. Furthermore, for the first time a 24 bp deletion was observed in three cases that may provide further insight into the structural basis for the abnormal function of SRSF2. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Chronic Myelomonocytic Leukemia Is Associated with More Frequent and More Rapid Progression to Acute Myeloid Leukemia and Shorter Survival Than Myelodysplastic Syndrome, but Is Less Frequently Treated: Analysis of Surveillance Epidemiology and End Results Data Linked to Medicare Enrollment Claims

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2784-2784
Author(s):  
Dan Zandberg ◽  
Ting-Ying Huang ◽  
Xuehua Ke ◽  
Maria R. Baer ◽  
Steven D. Gore ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Population Based ◽  
Chronic Myelomonocytic Leukemia ◽  
Rapid Progression ◽  
Hypomethylating Agents ◽  
Equity Ownership ◽  
Myelomonocytic Leukemia ◽  
Acute Myeloid

Abstract Abstract 2784 Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder that displays features of both a myelodysplastic syndrome (MDS) and a myeloproliferative neoplasm (MPN). Originally classified as an MDS subtype in the French-American-British (FAB) classification system, it was reclassified as an MDS/MPN in the World Health Organization (WHO) system. Based on SEER and NAACCR data, CMML is associated with shorter survival than MDS and MPN, but no other population-based data have been available to date. We used the Surveillance Epidemiology and End Results (SEER) dataset linked to Medicare enrollment and claims data to compare patient demographics, baseline characteristics, treatments received, progression to acute myeloid leukemia (AML) and survival between CMML and MDS. The sample included 792 CMML and 6,588 MDS patients diagnosed from 2001 through 2005. MDS cases were 34.6% low-risk [RA, RARS, RCMD, del (5q)], 13.7% high-risk (RAEB), 1.4% therapy-related and 50.4% not otherwise specified. CMML and MDS patients did not differ in age (peak proportion at 80–84 years in both) or race distribution (90% and 88% white non-Hispanic, respectively). Male predominance was greater in CMML than in MDS (59.2% vs. 53.8%; p =.004). Baseline renal disease was more common among CMML patients (13.0% vs. 7.4%; p <.0001), while CHF/ischemic heart disease (37.4% vs. 44.6%; p =.000) and liver disease (2.8% vs.4.3%; p=.041) were more common in MDS. There was no difference in the proportion with poor performance status, diagnosis of other cancers within 5 years of CMML/MDS diagnosis, health care use prior to diagnosis or median household income. More CMML than MDS patients received no treatment (25.25% vs. 15.7%; p <.0001). Among patients who were treated, fewer CMML patients received blood transfusions (59.5% vs. 70.4%; p <.0001), erythropoiesis-stimulating agents (46.3% vs. 62.4; p <.0001) and granulocyte colony-stimulating factor (7.32% vs. 16.9%; p <.0001), while more CMML patients were treated with cytarabine (2.02 vs. 0.87; p =.002), etoposide (1.01 vs. 0.36%; p = 0.009) and bone marrow transplantation (1.14% vs. 0.47%; p =.016). There was no difference in treatment with hypomethylating agents between CMML and MDS patients (5.81% vs. 7.64%; p =.064). A higher percentage of CMML patients progressed to AML (42.6% vs. 16.3%; p < .0001) and progression occurred earlier (median 8 vs. 33 weeks; p < .0001). CMML patients had a lower survival probability at 1 year (51% vs. 66%; p <.0001) and at 3 years (19% vs. 37%; p <.0001), and a shorter median survival (13.3 vs. 24 months; p <.0001). Survival remained significantly lower across gender, age and race groups. In this population-based study, we have demonstrated that CMML patients less frequently receive therapeutic interventions, in relation to MDS patients, but in fact have a higher rate of progression to AML, more rapid progression to AML and shorter survival. The percentages of patients receiving hypomethylating agents for both diseases was low in our dataset and has likely increased following FDA approval of azacitidine in 2004 and decitabine in 2006. Our data support early application of disease-modifying therapies in CMML, and also support the need for clinical trials focused on this disease entity. Disclosures: Gore: Celgene: Consultancy, Equity Ownership, Research Funding. Davidoff:Cellgene: Equity Ownership, Research Funding.

Dysregulation of RUNX1 Plays a Critical Role in the Progression of Myelodysplastic Syndromes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4108-4108
Author(s):  
Hiroko Sakurai ◽  
Yuka Harada ◽  
Hirotaka Matsui ◽  
Hideaki Nakajima ◽  
Toshio Kitamura ◽  
...  
Keyword(s):  
Splice Site ◽  
Myelodysplastic Syndromes ◽  
Critical Role ◽  
Gene Mutations ◽  
Splicing Factor ◽  
Expression Level ◽  
Dominant Negative Effect ◽  
Rapid Progression ◽  
Myeloid Neoplasms ◽  
Cd34 Cells

Abstract RUNX1/AML1 mutations have been frequently detected in patients with myeloid neoplasms, especially myelodysplastic syndromes (MDS) and chronic monocytic leukemia (CMML). Although the mutations have been analyzed thoroughly, its expression level has not been investigated. Therefore, we attempt to clarify the expression of RUNX1 in the pathogenesis of myeloid neoplasms. The study was approved by the institutional review board and patients gave written informed consent for the study, according to the Declaration of Helsinki. Several isoforms of RUNX1 mRNA are known and we analyzed RUNX1a (including exon 7a which has stop codon) and RUNX1b (skipping exon 7a and including exon 7b and 8). Expression levels of full length isoform (RUNX1b) and short isoform (RUNX1a which has a dominant negative effect on RUNX1b) in CD34+ cells from patients with myeloid neoplasms were examined. A part of patients with MDS or myelodysplastic syndrome / myeloproliferative neoplasms (MDS/MPN) including CMML showed RUNX1a overexpression. Average of relative RUNX1a expression level in MDS patients (n=34) and MDS/MPN patients (n=20) was 7.4-fold and 8.6-fold of the level in normal bone marrow (BM), respectively, whereas most of these patients showed almost same or slight increase of expression level of RUNX1b compared with normal BM. Interestingly, some patients showed high expression of RUNX1a and repression of RUNX1b. In both disease categories, patients with excess blasts displayed a significantly higher expression level of RUNX1a compared with normal BM and patients without excess blasts. During the disease progression in a single patient with MDS or MDS/MPN, the expression of RUNX1a became higher, while azacitidine treatment reduced RUNX1a expression. Genomic mutations of RUNX1 were also examined. RUNX1 mutations were detected in 16% of MDS and 35% of MDS/MPN. Surprisingly, a part of patients had both RUNX1 gene mutation and RUNX1a overexpression, and they showed rapid progression of disease. To evaluate the effects of RUNX1a overexpression, RUNX1a was transduced into CD34+ cells from MDS patients with low expression level of RUNX1a. RUNX1a-transduction resulted in cell proliferation on MS5 stromal cells. These results indicate that overexpression of RUNX1a may add growth advantage to CD34+ cells in patients with MDS or MDS/MPN. We next analyzed the mechanism of RUNX1a overexpression. Gene mutations affecting exon recognition were examined in the patients. Splicing factor mutations, SRSF2 and U2AF1, were detected frequently in MDS (15%) and MDS/MPN (50%). Patients with splicing factor mutations showed higher RUNX1a expression than patients without the mutations. To confirm that the splicing factor mutations affect the expression of RUNX1a, we performed enforced expression of SRSF2 p.P95H mutant using pMYs.IRES.EGFP retrovirus vector in a MDS-derived cell line, TF-1. After a single cell sorting, independent 13 expanding clones were analyzed. Most of the clones demonstrated higher expression of RUNX1a than mock cells, whereas RUNX1b expression was reduced in all clones. Increase of RUNX1a expression in SRSF2 mutant-transduced TF-1 cells was also confirmed by Western blot. Moreover, the clones with higher GFP intensity showed higher expression level of RUNX1a, suggesting that SRSF2 p.P95H expression level may affect the expression level of RUNX1a. Furthermore, SRSF2 mutant-transduced TF-1 cells showed phenotypic changes of higher CD11b and CD14 than mock TF-1 cells, suggesting that SRSF2 mutant may induce monocytic differentiation via RUNX1a overexpression. Gene mutations of RUNX1 in intron 6 and exon 7a were also analyzed. A 5' splice site change just after exon 6 was detected in a CMML patient with RUNX1a overexpression, which may be another mechanism of RUNX1a overexpression. Mutations of exon 7a or changes in 3' splice site just before exon 7a have not been detected yet. In conclusion, our data suggest that overexpression of RUNX1a may play a critical role in the progression of MDS and MDS/MPN, in addition to RUNX1 mutations. Splicing factor mutations are suspected to contribute to the mechanism of the dysregulation of RUNX1. Disclosures No relevant conflicts of interest to declare.

Loss Of p53 Promotes Transformation Of Oncogenic Nras-Induced Chronic Myelomonocytic Leukemia To An Acute Phase

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3790-3790
Author(s):  
Jingfang Zhang ◽  
Yangang Liu ◽  
Guangyao Kong ◽  
Yuan-I Chang ◽  
Erik A. Ranheim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Median Survival ◽  
Bone Marrow Cells ◽  
Chronic Myelomonocytic Leukemia ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Myelomonocytic Leukemia ◽  
Acute Myeloid ◽  
Marrow Cells ◽  
Myeloid Progenitors

Abstract Chronic myelomonocytic leukemia (CMML) primarily occurs in the elderly with the median age ranging from 65 to 75 years. As defined by WHO, CMML is characterized by persistent monocytosis in peripheral blood, hepatosplenomegaly, and the absence of BCR-ABL fusion gene. CMML is a devastating cancer for multiple reasons, one of which is that approximately 20% of CMML cases evolve into acute myeloid leukemia (AML) soon after their first diagnosis. However, little is known about the cellular and molecular mechanisms underlying this malignant transformation. Recently, our lab developed a CMML mouse model induced by oncogenic NrasG12D/+ expressed from its endogenous locus. Above 90% of recipient mice with NrasG12D/+ bone marrow cells developed CMML-like phenotypes with a median survival of ∼56 weeks. Interestingly, none of these mice spontaneously transform to AML. To identify the pathogenetic origins underlying CMML transformation to AML, we further deleted p53 expression in NrasG12D/+ bone marrow cells using p53fl/fl allele and Mx1-Cre because deletion of p53 is a common genetic event observed in oncogenic Ras-driven cancers. We found that ERK1/2 is significantly hyperactivated in NrasG12D/+; p53-/- hematopoietic stem/progenitor cells (enriched for myeloid progenitors) in the absence of cytokines or in the presence of low concentration of GM-CSF. Concomitantly, the mutant myeloid progenitors show significantly increased self-renewal in a serial replating assay in vitro. We transplanted NrasG12D/+, p53-/-, or NrasG12D/+; p53-/- bone marrow cells into lethally irradiated mice. Unlike recipients with p53-/- cells that died of a T-cell disease with 100% penetrance and a median survival of 24 weeks, ∼70% of recipients with NrasG12D/+; p53-/- cells died of AML or acute myeloid sarcoma with a median survival of 16 weeks. These malignant myeloid diseases are transplantable in secondary recipients. Interestingly, only mutant hematopoietic stem cells (HSCs) could initiate and maintain leukemia phenotypes in the NrasG12D/+ induced CMML model, whereas both NrasG12D/+; p53-/- HSCs and myeloid progenitors could initiate AML or acute myeloid sarcoma. Our results indicate that deletion of p53 cooperates with NrasG12D/+ mutation to transform CMML into an acute phase. This malignant transformation is initiated by mutant myeloid progenitors, which show increased self-renewal and potentially serve as leukemia initiating cells. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document