Frequency of Hematologic and Solid Malignancies in the Family History of Patients with Myeloid Neoplasms

Background: Studies demonstrated that there are several germline mutations that lead to a familial predisposition for acute myeloid leukemia and Myelodysplastic syndrome. According to the American Society of Clinical Oncology, the minimum cancer family history was defined as including first- and second-degree family history, type of primary cancer, and age at diagnosis. The current study aimed to estimate the frequency of positive family history for hematologic and solid malignancies in patients with Myeloid Neoplasms / Aplastic anemia. Patients and Methods: A cross-section study was carried out at the Center of Blood Diseases, Medical City Campus during the period from March-December 2020. A purposeful sample of all adult patients with Myeloid Neoplasms [Acute Myeloid Leukemia, Myelodysplastic Syndrome, Chronic Myeloid Leukemia, and Aplastic Anemia] was included in the study. A data collection form was prepared, based on the Hereditary Hematopoietic Malignancies Screening form adopted by the University of Chicago, and modified by the researchers; The data were collected by direct interview with the patients. Patients with hematologic malignancy and one or more first-degree relatives, or ≥2 second-degree relatives, with hematologic malignancies and individuals with Myelodysplastic Syndrome or Acute Myeloid Leukemia and two first or second-degree relatives with a diagnosis of solid tumor malignancy, were considered potential carriers of such genetic predisposition. Results: A total of 153 patients were included; males were nearly equal to females with a male to female ratio of nearly 1:1. Acute Myeloid Leukemia was found in 57.5%, Aplastic Anemia was found in 19%, Chronic Myeloid Leukemia in 17% and only four patients (6.5%) were known cases of Myelodysplastic Syndrome. Nine patients (5.9%) reported a family history of hematological malignancies, 29 (19.0%) reported a family history of solid malignancies and only one patient reported a family history of both hematological and solid malignancies. Regarding the official medical reports of the patients, no patient had been interviewed properly about this crucial point. Conclusion: Positive family history for hematological and solid malignancies in Iraqi patients with myeloid neoplasms is prevalent. Our current approach to this critical issue in Iraq needs to be re-considered.

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

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.

Incidence of myeloid neoplasms in Spain (2002–2013): a population-based study of the Spanish network of cancer registries

Comprehensive population-based data on myeloid neoplasms (MNs) are limited, mainly because some subtypes were not recognized as hematological cancers prior to the WHO publication in 2001, and others are too rare to allow robust estimates within regional studies. Herein, we provide incidence data of the whole spectrum of MNs in Spain during 2002–2013 using harmonized data from 13 population-based cancer registries. Cases (n = 17,522) were grouped following the HAEMACARE groupings and 2013-European standardized incidence rates (ASRE), incidence trends, and estimates for 2021 were calculated. ASRE per 100,000 inhabitants was 5.14 (95% CI: 5.00–5.27) for myeloproliferative neoplasms (MPN), 4.71 (95% CI: 4.59–4.84) for myelodysplastic syndromes (MDS), 3.91 (95% CI: 3.79–4.02) for acute myeloid leukemia, 0.83 (95% CI: 0.78–0.88) for MDS/MPN, 0.35 (95% CI: 0.32–0.39) for acute leukemia of ambiguous lineage, and 0.58 (95% CI: 0.53–0.62) for not-otherwise specified (NOS) cases. This study highlights some useful points for public health authorities, such as the remarkable variability in incidence rates among Spanish provinces, the increasing incidence of MPN, MDS, and MDS/MPN during the period of study, in contrast to a drop in NOS cases, and the number of cases expected in 2021 based on these data (8446 new MNs).

Genomic studies controvert the existence of the CUX1 p75 isoform

CUX1, encoding a homeodomain-containing transcription factor, is recurrently deleted or mutated in multiple tumor types. In myeloid neoplasms, CUX1 deletion or mutation carries a poor prognosis. We have previously established that CUX1 functions as a tumor suppressor in hematopoietic cells across multiple organisms. Others, however, have described oncogenic functions of CUX1 in solid tumors, often attributed to truncated CUX1 isoforms, p75 and p110, generated by an alternative transcriptional start site or post-translational cleavage, respectively. Given the clinical relevance, it is imperative to clarify these discrepant activities. Herein, we sought to determine the CUX1 isoforms expressed in hematopoietic cells and find that they express the full-length p200 isoform. Through the course of this analysis, we found no evidence of the p75 alternative transcript in any cell type examined. Using an array of orthogonal approaches, including biochemistry, proteomics, CRISPR/Cas9 genomic editing, and analysis of functional genomics datasets across a spectrum of normal and malignant tissue types, we found no data to support the existence of the CUX1 p75 isoform as previously described. Based on these results, prior studies of p75 require reevaluation, including the interpretation of oncogenic roles attributed to CUX1.

Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition

Myeloid neoplasms with germline predisposition have recently been added as distinct provisional entities in the 2017 revision of the World Health Organization’s classification of tumors of hematopoietic and lymphatic tissue. Individuals with germline predisposition have increased risk of developing myeloid neoplasms—mainly acute myeloid leukemia and myelodysplastic syndrome. Although the incidence of myeloid neoplasms with germline predisposition remains poorly defined, these cases provide unique and important insights into the biology and molecular mechanisms of myeloid neoplasms. Knowledge of the regulation of the germline genes and their interactions with other genes, proteins, and the environment, the penetrance and clinical presentation of inherited mutations, and the longitudinal dynamics during the process of disease progression offer models and tools that can further our understanding of myeloid neoplasms. This knowledge will eventually translate to improved disease sub-classification, risk assessment, and development of more effective therapy. In this review, we will use examples of these disorders to illustrate the key molecular pathways of myeloid neoplasms.

PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword

Despite recent discoveries and therapeutic advances in aggressive myeloid neoplasms, there remains a pressing need for improved therapies. For instance, in acute myeloid leukemia (AML), while most patients achieve a complete remission with conventional chemotherapy or the combination of a hypomethylating agent and venetoclax, de novo or acquired drug resistance often presents an insurmountable challenge, especially in older patients. Poly(ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2, are involved in detecting DNA damage and repairing it through multiple pathways, including base excision repair, single-strand break repair, and double-strand break repair. In the context of AML, PARP inhibitors (PARPi) could potentially exploit the frequently dysfunctional DNA repair pathways that, similar to deficiencies in homologous recombination in BRCA-mutant disease, set the stage for cell killing. PARPi appear to be especially effective in AML with certain gene rearrangements and molecular characteristics (RUNX1-RUNX1T1 and PML-RARA fusions, FLT3- and IDH1-mutated). In addition, PARPi can enhance the efficacy of other agents, particularly alkylating agents, TOP1 poisons, and hypomethylating agents, that induce lesions ordinarily repaired via PARP1-dependent mechanisms. Conversely, emerging reports suggest that long-term treatment with PARPi for solid tumors is associated with an increased incidence of myelodysplastic syndrome (MDS) and AML. Here, we (i) review the pre-clinical and clinical data on the role of PARPi, specifically olaparib, talazoparib, and veliparib, in aggressive myeloid neoplasms and (ii) discuss the reported risk of MDS/AML with PARPi, especially as the indications for PARPi use expand to include patients with potentially curable cancer.