Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults. It is an aggressive hematologic neoplasm, with a bimodal age distribution typically presenting in childhood and ...the 6th decade of life (Terwilliger and Abdul-Hay, 2017). Renal injury in ALL is common and can occur through many different mechanisms, such as prerenal acute kidney injury, acute tubular necrosis, renovascular disease, obstruction, glomerulonephritis, and parenchymal infiltration of tumor cells (Luciano and Brewster, 2014). Infiltration of kidneys by leukemia cells is common; however a resultant injury only occurs in about 1% of patients, and renal failure is even more rare (Luciano and Brewster, 2014). Renal failure due to bilateral infiltration of tumor cells has been reported in only a few cases and is thought to be a poor prognostic indicator (Luciano and Brewster, 2014; Sherief et al., 2015). Biopsy is essential to the diagnosis of renal infiltration of leukemia. We present a case of acute renal failure secondary to bilateral renal infiltration of ALL presenting as the first sign of relapse in a young man.
Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem cell malignancies that can phenotypically resemble other hematologic disorders. Thus, tools that may add to current diagnostic ...practices could aid in disease discrimination. Constitutive innate immune activation is a pathogenetic driver of ineffective hematopoiesis in MDS through Nod-like receptor protein 3 (NLRP3)–inflammasome-induced pyroptotic cell death. Oxidized mitochondrial DNA (ox-mtDNA) is released upon cytolysis, acts as a danger signal, and triggers inflammasome oligomerization via DNA sensors. By using immortalized bone marrow cells from murine models of common MDS somatic gene mutations and MDS primary samples, we demonstrate that ox-mtDNA is released upon pyroptosis. ox-mtDNA was significantly increased in MDS peripheral blood (PB) plasma compared with the plasma of healthy donors, and it was significantly higher in lower-risk MDS vs higher-risk MDS, consistent with the greater pyroptotic cell fraction in lower-risk patients. Furthermore, ox-mtDNA was significantly higher in MDS PB plasma compared with all other hematologic malignancies studied, with the exception of chronic lymphocytic leukemia (CLL). Receiver operating characteristic/area under the curve (ROC/AUC) analysis demonstrated that ox-mtDNA is a sensitive and specific biomarker for patients with MDS compared with healthy donors (AUC, 0.964), other hematologic malignancies excluding CLL (AUC, 0.893), and reactive conditions (AUC, 0.940). ox-mtDNA positively and significantly correlated with levels of known alarmins S100A9, S100A8, and apoptosis-associated speck-like protein containing caspase recruitment domain (CARD) specks, which provide an index of medullary pyroptosis. Collectively, these data indicate that quantifiable ox-mtDNA released into the extracellular space upon inflammasome activation serves as a biomarker for MDS and the magnitude of pyroptotic cell death.
•ox-mtDNA is released from cells after lytic, pyroptotic cell death and is readily quantifiable in cell supernatants and patient plasma.•PB plasma glucose–adjusted ox-mtDNA concentration is a sensitive and specific biomarker for MDS and medullary cell death.
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Deletion 5q MDS: Molecular and therapeutic implications Komrokji, Rami S., MD; Padron, Eric, MD; Ebert, Benjamin L., MD ...
Best practice & research. Clinical haematology,
12/2013, Letnik:
26, Številka:
4
Journal Article
Recenzirano
Heterozygous, interstitial deletions of chromosome 5q are the most common cytogenetic abnormality in myelodysplastic syndromes (MDS). This chromosomal abnormality is associated with a consistent ...clinical phenotype, the 5q- syndrome, in a subset of patients, and therapeutic sensitivity to the drug lenalidomide. No genes on chromosome 5q undergo recurrent homozygous inactivation in MDS patients. Instead, haploinsufficiency for key genes powerfully alters hematopoiesis, leading to the MDS phenotype in patients with del(5q). Haploinsufficiency for the RPS14 gene leads to activation of the p53 pathway and the macrocytic anemia characteristic of this disorder, and loss of p53 rescues erythropoiesis and facilitates clonal progression. Other genes, as well as miR-145 and miR-146a , contribute to aberrant megakaryopoiesis and a selective advantage for the del(5q) clone. The integrated effects of haploinsufficiency for these key genes, in aggregate, lead to the full phenotype of the disorder.
Hispanic patients have been reported to have an increased incidence of AML and possibly inferior outcomes compared to non‐Hispanics. We conducted a retrospective study of 225 AML patients (58 ...Hispanic and 167 non‐Hispanic) at two academic medical centers in Florida. Disease characteristics, cytogenetics, mutation profiles, and clinical outcomes were assessed. Hispanic patients were younger at presentation than non‐Hispanics (p = 0.0013). We found associations between single gene mutations and ethnicity, with IDH1 mutations being more common in non‐Hispanics (95.2% vs. 4.8%, p = 0.0182) and WT1 mutations more common in Hispanics (62.5% vs. 37.5%, p = 0.0455). We also found an emerging trend towards adverse risk cytogenetics in Hispanic patients (p = 0.1796), as well as high risk fusions such as MLL‐r (70% vs. 30%, p = 0.004). There was no difference in overall survival (OS) between Hispanic and non‐Hispanics patients. When examining only newly diagnosed patients (n = 105), there was improved OS in Hispanics (median 44.7 months vs. 14 months, p = 0.026) by univariate analysis and equivalent OS by multivariate analysis (hazard ratio = 1.52 95% CI = 0.74–3.15). Hispanics with a driver mutation not class‐defining had improved survival compared to non‐Hispanics. Our study demonstrates significant genetic differences between Floridian Hispanics and non‐Hispanics, but no difference in OS in patients treated at an academic medical center.
The myelodysplastic/myeloproliferative neoplasms （MDS/MPNs） are a unique group of hematologic malignancies characterized by concomitant myelodysplastic and myeloproliferative features. According to ...the 2008 WHO classification, the category includes atypical chronic myeloid leukemia （aCML）, chronic myelomonocytic leukemia （CMML）, juvenile myelomonocytic leukemia （JMML）, MDS/MPN-unclassifiable （MDS/MPN-U）, and the provisional entity refractory anemia with ring sideroblasts and thrombocytosis （RARS-T）. Although diagnosis currently remains based on clinicopathologic features, the incorporation of next- generation platforms has allowed for the recent molecular characterization of these diseases which has revealed unique and complex mutational profiles that support their distinct biology and is anticipated to soon play an integral role in diagnosis, prognostication, and treatment. Future goals of research should include the development of disease-modifying therapies, and further genetic understanding of the category will likely form the foundation of these efforts.
Many prognostic scoring systems have been developed for chronic myelomonocytic leukemia (CMML). Although these efforts have been informative, no single model has been considered the consensus for ...CMML prognostication and all models are only moderately prognostic. CMML clinical models utilize mainly hematology and morphology parameters to estimate risk. A better understanding of cytogenetics and the genomic landscape of CMML have resulted in integrated risk models such as CMML Prognostic Scoring System (CPSS)-Mol and Mayo Molecular that may provide better prognostic accuracy for an individual patient. For example, frameshift/nonsense ASXL1 mutations have been consistently shown to confer inferior outcomes leading to its incorporation into some of the major risk classification systems. Prognostication in the setting of therapeutic interventions such as hypomethylating agents and allogeneic hematopoietic cell transplantation have also garnered considerable interest. Despite having many validated risk models available, not a single system is universally adopted. Herein, we will provide an overview of how these systems evolved and progress toward a uniform system.
Purpose
The advent of next-generation sequencing has allowed for the annotation of a vast array of recurrent somatic mutations across human malignancies, ushering in a new era of precision oncology. ...Chronic myelomonocytic leukemia is recognized as a myelodysplastic/myeloproliferative neoplasm and displays heterogenous clinical and genetic features. Herein, we review what is currently understood regarding the genomic landscape of this disease and discuss how somatic mutations have impacted current risk stratification methods.
Recent Findings
Genomic studies in chronic myelomonocytic leukemia have identified a characteristic spectrum of cytogenetic and molecular abnormalities. Chromosomal abnormalities are detected in ~30% of patients and somatic gene mutations in up to 90% of patients, most commonly in
TET2, SRSF2,
and
ASXL1.
While cytogenetic abnormalities have long been known to impact the prognosis of myeloid neoplasms, recent studies have identified that somatic mutations impact prognosis independent of cytogenetic and clinical variables. This is best exemplified by mutations in
ASXL1
, which have been uniformly associated with inferior survival. These findings have led to the development of three molecularly inspired prognostic models, in an attempt to more accurately prognosticate in the disease.
Summary
Our understanding of the genomic landscape of chronic myelomonocytic leukemia continues to evolve, with somatic mutations demonstrating an expanding role in diagnosis, risk stratification, and therapeutic decision-making. Given these findings, molecular profiling by next-generation sequencing should be considered standard of care in all patients.
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