Inflammation-related genes S100s, RNASE3, and CYBB and risk of leukemic transformation in patients with myelodysplastic syndrome with myelofibrosis

AbstractMyelodysplastic syndrome with myelofibrosis (MDS-MF) has been associated with an inferior prognosis compared with MDS without MF. However, MDS-MF is not listed independently as a subtype of MDS, and its clinical and genetic characteristics remain poorly understood. We retrospectively compared 53 patients with MDS-MF (44 MF grade 1/MF1; 9 MF grade 2–3/MF2 − 3) and 31 with de novo MDS without MF (MDS). The leukemic transformation risks of both MDS-MF2 − 3 and MDS-MF1 were increased compared with the MDS group. To identify the potential mechanisms responsible for the leukemic transformation of MDS-MF, we performed single-cell sequencing for one MDS-MF2 − 3 patient before and after leukemic transformation to explore the variations in gene expression levels. In addition to upgraded expression levels of acute myeloid leukemia-related genes during leukemic transformation, expression levels of some inflammation-related genes (such as S100s, RNASE3, and CYBB) were also increased, and inflammation-related pathways were up-regulated. These results suggest that inflammation-related genes and pathways may play an important role in the leukemic transformation of MDS-MF.

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A Case of Myeloid Sarcoma in the Nasal Cavity Occurred in the Patient with Leukemic Transformation in Myelodysplastic Syndrome

Korean Journal of Otorhinolaryngology - Head and Neck Surgery ◽

10.3342/kjorl-hns.2019.00017 ◽

2020 ◽

Vol 63 (2) ◽

pp. 81-84

Author(s):

Dong Hoo Lee ◽

Sung Yool Park ◽

Ha Young Park ◽

Seong Kook Park

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Nasal Cavity ◽

Myeloid Leukemia ◽

Rare Case ◽

De Novo ◽

Myeloid Sarcoma ◽

Leukemic Transformation ◽

Normal Architecture ◽

Acute Myeloid

Myeloid sarcoma is characterized by the presence of myeloid blasts at an extramedullar site that disrupts the normal architecture of the organ. Many of these cases are associated with acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or occur in de novo. It occurs most commonly in skin, lymph node, gastrointestinal tract, bone, soft tissue but, rarely in head and neck; especially in nasal cavity. Therefore, it is often misdiagnosed as a different disease: most commonly as lymphoma. Here we report a rare case of myeloid sarcoma in the nasal cavity that occurred in a patient with leukemic transformation with myelodysplastic syndrome, provided with literature review.

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Jumping Translocations of 1q in Myelodysplastic Syndrome and Acute Myeloid Leukemia: Report of Three Cases and Review of Literature

Case Reports in Genetics ◽

10.1155/2018/8296478 ◽

2018 ◽

Vol 2018 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

T. Couture ◽

K. Amato ◽

A. DiAdamo ◽

P. Li

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

De Novo ◽

Pericentromeric Region ◽

Review Of Literature ◽

Cell Lineages ◽

Chromosome 1Q ◽

Acrocentric Chromosomes ◽

Acute Myeloid

Jumping translocations of 1q refer to the break-off of chromosome 1q as a donor fusing to two or more recipient chromosomes. We detected jumping translocations of 1q in three patients with initial diagnosis of myelodysplastic syndrome (MDS) and later progression to acute myeloid leukemia (AML). Review of literature found jumping translocations of 1q in 30 reported cases of MDS and AML. The cytogenetic findings from these 33 cases showed that seven cases had a stemline clone and 26 cases had de novo jumping translocations of 1q in which 5% of cell lineages had additional structural rearrangements. In 75% of cases, the 1q donor jumped to the short arm of recipient acrocentric chromosomes. Approximately 82% of the fusions occurred in the telomeric regions of short and long arms and 18% occurred in the pericentric or interstitial regions of recipient chromosomes. Hypomethylation of the donor 1q pericentromeric region and shortened telomeres in recipient chromosomes were associated with the formation of jumping translocations. Jumping translocations of 1q as an indication of chromosomal instability pose high risk for progression of MDS to AML and a poor prognosis. Further understanding of underlying genomic defects and their clinical significance will improve overall treatment and patient care.

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Acute myeloid leukemia and myelodysplastic syndrome in children treated for cancer: comparison with primary presentation

Blood ◽

10.1182/blood.v100.2.427 ◽

2002 ◽

Vol 100 (2) ◽

pp. 427-434 ◽

Cited By ~ 47

Author(s):

Dorothy R. Barnard ◽

Beverley Lange ◽

Todd A. Alonzo ◽

Jonathan Buckley ◽

J. Nathan Kobrinsky ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

De Novo ◽

Latency Period ◽

Disease Free Survival ◽

Free Survival ◽

Cell Counts ◽

Acute Myeloid

Abstract There has not been a reported series of children with therapy-induced myelodysplastic syndrome/acute myeloid leukemia (tMDS/tAML) who were treated systematically. This paper describes 24 children with tMDS/tAML who were assigned randomly to standard- or intensive-timing induction on protocol CCG 2891. Presenting features and outcomes of those children were compared with those of 960 patients with de novo MDS (62 patients) or AML (898 patients). Children with tMDS/tAML were older at presentation (P = .015), had lower white blood cell counts (P = .01), and were more likely to have MDS (21% vs 7%) (P = .02) and trisomy 8 (P = .06). Fewer had hepatomegaly (P = .02), splenomegaly (P = .03), hepatosplenomegaly (P = .02), or classic AML translocations [t(8;21), t(15;17), 16q22; P = .02]. They had a poorer induction rate (50% vs 72%,P = .016), overall survival (26% vs 47% at 3 years,P = .007), and event-free survival (21% vs 39% at 3 years, P =.023). Disease-free survival after achieving remission was similar (45% vs 53%, P = .868). Children with tMDS/tAML who received intensive-timing induction had better outcomes than those who received standard-timing induction (overall survival 32% vs 0%, P = .54). In this study, the latency period to development of tMDS/tAML was the same for presumed alkylator-induced as for topoisomerase-induced myeloid leukemia. The findings of this study confirm that most children with tMDS/tAML have disease resistant to current therapies. Standard-timing induction appears less effective for this population.

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Transcription Factors LEF1, PU.1 and IRF8 Have Decreased Expression Levels in Majority of De Novo Acute Myeloid Leukemia Patients

World Family Medicine Journal/Middle East Journal of Family Medicine ◽

10.5742/mewfm.2018.93264 ◽

2018 ◽

Vol 16 (2) ◽

pp. 207-217

Author(s):

Fatemeh Salarpour ◽

Kourosh Goudarzipour ◽

Mohammad Hossein Mohammadi

Keyword(s):

Acute Myeloid Leukemia ◽

Transcription Factors ◽

Myeloid Leukemia ◽

De Novo ◽

Expression Levels ◽

Acute Myeloid

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MYC Expression Is Prognostic in Therapy Related Acute Myeloid Leukemia (AML) and AML with Myelodysplastic Syndrome (MDS)-Related Changes

Blood ◽

10.1182/blood.v124.21.5334.5334 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5334-5334

Author(s):

Maro Ohanian ◽

Uri Rozovski ◽

Hagop M. Kantarjian ◽

Sanam Loghavi ◽

Yang O. Huh ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Protein Expression ◽

Myelodysplastic Syndrome ◽

Clinical Significance ◽

Myeloid Leukemia ◽

Normal Karyotype ◽

Newly Diagnosed ◽

Expression Levels ◽

Previously Treated ◽

Acute Myeloid

Abstract Background: MYC mRNA overexpression has been described in acute myeloid leukemia (AML), but no studies have assessed MYC protein expression in AML where its clinical significance is unknown. In this study our aim is to assess MYC protein expression across all AML subtypes and explore its prognostic value in in a subset of patients (pts) with particularly poor prognosis, namely those with AML with myelodysplastic syndrome (MDS)-related changes (AML-MRC) and therapy-related AML (t-AML). Characterized by unfavorable cytogenetics, the prognosis of patients with AML-MRC and t-AML is often dismal, even in patients who undergo allogeneic stem cell transplant. There is a need for further molecular characterization of AML-MRC and t-AML to identify prognostic markers to optimally risk-stratify to better guide treatment decisions in these pts. Objectives: In the current study we sought to: (1) assess MYC protein expression by immunohistochemistry (IHC) performed on bone marrow (BM) specimens of pts with all types of AML, including acute promyelocytic leukemia (APL), and myelodysplastic syndromes (MDS), and (2) explore the prognostic significance of MYC protein expression in AML-MRC and t-AML (2008 WHO criteria). Methods: MYC protein expression was assessed by IHC on BM obtained from pts with AML, APL, and MDS, and from patients without hematologic neoplasms (normal controls). MYC expression was considered positive if > 5% blasts in BM showed nuclear reactivity. For cases classified as t-AML and AML-MRC by WHO 2008, MYC expression was correlated with molecular, cytogenetic, and clinical outcome data. X-tile software was used to identify the optimal cutoff point to dichotomize pts by MYC protein expression. Results: We evaluated BM MYC expression in 306 pts during 2006-2013 with newly diagnosed AML (n=246) or APL (n=11), previously treated AML (induction failure or relapse) (n=30), MDS (n=19), AML-MRC (n=68), t-AML (n=10), and normal BM (n=11). The median age was 61 yrs (13-88) with 54% men. Normal BM showed negligible MYC expression, ≤2% positive nuclei. The median MYC expression varied across diseases: newly diagnosed AML 25% (range 0-38%), APL 50% (range 19-75%), previously treated AML 20% (range 0-80), MDS 5% (range 0-30%) (differences between groups, p=0.0001). High MYC expression correlated with high LDH (rs = 0.285, p<0.0001), WBC (rs = 0.225, p<0.0001) and BM blasts (rs 0.417, p<0.0001). Among newly diagnosed AML pts 20 had normal MYC expression ≤ 2%. MYC rearrangement by FISH was not detected in tested normal karyotype AML cases with variable MYC expression levels. MYC rearrangement by FISH was not detected in tested normal karyotype AML cases with variable MYC expression levels. The clinical significance of MYC expression was examined in 78 pts with previously untreated AML-MRC and t-AML (59% men, median age 64 years). Pts with MYC expression above a determined cutoff of 21% had a significantly worse median overall survival (OS) of 8 months compared to 17 months in those with MYC ≤ 21% (p=0.035). Disease free survival (DFS) was also inferior in pts with higher MYC expression. Median DFS was 3 months in pts with MYC >21% and 8 months for pts with MYC ≤ 21% (p=0.064). The rate of CR was 63% in pts with MYC≤ 21% and 37% in those >21%, however this difference was not statistically significant. In pts with newly diagnosed AML-MRC and t-AML, high MYC expression did not correlate with markers of proliferation (high LDH, WBC and BM blasts). Furthermore, MYC levels were similar across karyotypes: trisomy 8 (where MYC resides), complex, and core binding factors. Conclusion: MYC protein expression is a strong predictor of survival and an important biomarker of prognosis in patients with t-AML and AML-MRC. On BM IHC, pts with >21% MYC-positive blasts have an inferior OS, DFS, and remission rate than pts with ≤ 21% MYC-positive blasts. Increased MYC protein expression is independent of rearrangement status by FISH. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia

Blood ◽

10.1182/blood-2011-05-353185 ◽

2011 ◽

Vol 118 (22) ◽

pp. 5905-5913 ◽

Cited By ~ 52

Author(s):

Anna Staffas ◽

Meena Kanduri ◽

Randi Hovland ◽

Richard Rosenquist ◽

Hans Beier Ommen ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Prognostic Markers ◽

Npm1 Mutation ◽

Mutation Status ◽

Expression Levels ◽

Pediatric Aml ◽

Gene Expression Levels ◽

Acute Myeloid

Abstract Mutation status of FLT3, NPM1, CEBPA, and WT1 genes and gene expression levels of ERG, MN1, BAALC, FLT3, and WT1 have been identified as possible prognostic markers in acute myeloid leukemia (AML). We have performed a thorough prognostic evaluation of these genetic markers in patients with pediatric AML enrolled in the Nordic Society of Pediatric Hematology and Oncology (NOPHO) 1993 or NOPHO 2004 protocols. Mutation status and expression levels were analyzed in 185 and 149 patients, respectively. Presence of FLT3-internal tandem duplication (ITD) was associated with significantly inferior event-free survival (EFS), whereas presence of an NPM1 mutation in the absence of FLT3-ITD correlated with significantly improved EFS. Furthermore, high levels of ERG and BAALC transcripts were associated with inferior EFS. No significant correlation with survival was seen for mutations in CEBPA and WT1 or with gene expression levels of MN1, FLT3, and WT1. In multivariate analysis, the presence of FLT3-ITD and high BAALC expression were identified as independent prognostic markers of inferior EFS. We conclude that analysis of the mutational status of FLT3 and NPM1 at diagnosis is important for prognostic stratification of patients with pediatric AML and that determination of the BAALC gene expression level can add valuable information.

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Overexpression of BAMBI and SMAD7 impacts prognosis of acute myeloid leukemia patients: A potential TERT non-canonical role

Cancer Biomarkers ◽

10.3233/cbm-200927 ◽

2021 ◽

pp. 1-12

Author(s):

Miral Magdy Shehata ◽

Al-Aliaa Mohamed Sallam ◽

Mary Gamal Naguib ◽

Hala Osman EL-Mesallamy

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Transforming Growth Factor ◽

De Novo ◽

Transforming Growth Factor Β ◽

Expression Levels ◽

Real Time Quantitative Pcr ◽

Kaplan Meier ◽

De Novo Aml ◽

Acute Myeloid

BACKGROUND: Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) and mothers against decapentaplegic homolog 7 (SMAD7) are important transforming growth factor-β (TGF-β) signaling antagonists, however their roles in acute myeloid leukemia (AML) remains unclear. Telomerase reverse transcriptase (TERT) may be involved in regulating BAMBI and SMAD7 expressions; a role beyond telomeres that is not clinically validated yet. OBJECTIVE: In this study, we examined the expression levels and prognostic values of BAMBI, SMAD7 and TERT and their association with AML patients’ outcomes. METHODS: Blood samples were collected from 74 de-novo AML patients and 16 controls. Real-time quantitative PCR (qRT-PCR) was performed to analyze BAMBI, SMAD7 and TERT expressions. RESULTS: BAMBI and SMAD7 expression in AML were significantly upregulated versus controls (p< 0.05). BAMBI, SMAD7 and TERT levels were significantly correlated together (p< 0.001). Kaplan-Meier analysis indicated that patients with high BAMBI, SMAD7 and TERT expression levels had markedly shorter event free survival (EFS) and overall survival (OS) time (p< 0.01). Furthermore, multivariate analysis revealed that only high BAMBI expression was an independent risk factor for OS (p= 0.001). CONCLUSIONS: BAMBI is a novel biomarker in predicting prognosis in AML patients. Moreover, a potential interplay is found between BAMBI, SMAD7 and TERT in AML pathogenies.

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