Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape.

Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human diseases remains unexplored. Using isogenic cell lines, patient samples, and a mutant mouse model, we investigated how cancer-associated mutations in SF3B1 alter transcription. We found that these mutations reduce the elongation rate of RNA polymerase II (RNAPII) along gene bodies and its density at promoters. The elongation defect results from disrupted pre-spliceosome assembly due to impaired protein-protein interactions of mutant SF3B1. The decreased promoter-proximal RNAPII density reduces both chromatin accessibility and H3K4me3 marks at promoters. Through an unbiased screen, we identified epigenetic factors in the Sin3/HDAC/H3K4me pathway, which, when modulated, reverse both transcription and chromatin changes. Our findings reveal how splicing factor mutant states behave functionally as epigenetic disorders through impaired transcription-related changes to the chromatin landscape. We also present a rationale for targeting the Sin3/HDAC complex as a therapeutic strategy.

PD-1H/VISTA mediates immune evasion in acute myeloid leukemia.

Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics, such as targeted therapy and immunotherapy, including anti-programmed cell death protein (anti-PD) therapy. We demonstrate that programmed death-1 homolog (PD-1H), an immune coinhibitory molecule, is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells express PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell-mediated immune responses. Importantly, ablation of AML cell-surface PD-1H by antibody blockade or genetic knockout significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML progression, and the combination of PD-1H blockade with anti-PD therapy conferred a synergistic antileukemia effect. Our findings provide the basis for PD-1H as a potential therapeutic target for treating human AML.

Breakthrough invasive fungal infections on isavuconazole prophylaxis in hematologic malignancy & hematopoietic stem cell transplant patients.

BACKGROUND: Isavuconazole (ISA) is a newer antifungal used in patients with history of hematologic malignancies and hematopoietic transplant and cellular therapies (HM/TCT). Although it has a more favorable side-effect profile, breakthrough invasive fungal infections (bIFIs) while on ISA have been reported. METHODS: In this single-center retrospective study evaluating HM/TCT patients who received prophylactic ISA for ≥7 days, we evaluated the incidence and potential risk factors for bIFIs. RESULTS: We evaluated 106 patients who received prophylactic ISA. The patients were predominantly male (60.4%) with median age of 65 (range: 21-91) years. Acute myeloid leukemia (48/106, 45.3%) was the most common HM, with majority having relapsed and/or refractory disease (43/106, 40.6%) or receiving ongoing therapy (38/106, 35.8%). Nineteen patients (17.9%) developed bIFIs-nine proven [Fusarium (3), Candida (2), Mucorales plus Aspergillus (2), Mucorales (1), Colletotrichum (1)], four probable invasive pulmonary Aspergillus, and six possible infections. Twelve patients were neutropenic for a median of 28 (8-253) days prior to bIFI diagnosis. ISA levels checked within 7 days of bIFI diagnosis (median: 3.65 µg/mL) were comparable to industry-sponsored clinical trials. All-cause mortality among the bIFI cases was 47.4% (9/19).We also noted clinically significant cytomegalovirus co-infection in 5.3% (1/19). On univariate analysis, there were no significant differences in baseline comorbidities and potential risk factors between the two groups. CONCLUSION: ISA prophylaxis was associated with a significant cumulative incidence of bIFIs. Despite the appealing side-effect and drug-interaction profile of ISA, clinicians must be vigilant about the potential risk for bIFIs.

What constitutes meaningful improvement in myelodysplastic syndromes?

Myelodysplastic syndromes (MDS) are a heterogeneous spectrum of clonal stem cell disorders characterized by ineffective hematopoiesis and resulting peripheral blood cytopenias. Clinical manifestations of the disorder are varied and range from mild asymptomatic anemia to a markedly truncated life expectancy, underscoring the importance of risk-adapted therapy. MDS therapy for both lower- and higher-risk patients is an area of immense therapeutic opportunity. This is partly due to the diversity of treatment goals between patients and defining what constitutes meaningful benefit from a patient's viewpoint. Correlating metrics such as hematologic improvement or response rate to develop novel therapies can be falsely reassuring to physicians and patients, specifically if the interventions are burdensome, disconnected from a patient's sense of wellbeing and do not correlate with an improvement in quality of life or longevity. We discuss aligning drug development goals with patient goals that will lead to meaningful improvement in MDS clinical care.

In vivo anti-tumor effect of PARP inhibition in IDH1/2 mutant MDS/AML resistant to targeted inhibitors of mutant IDH1/2.

Treatment options for patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are scarce. Recurring mutations, such as mutations in isocitrate dehydrogenase-1 and -2 (IDH1/2) are found in subsets of AML and MDS, are therapeutically targeted by mutant enzyme-specific small molecule inhibitors (IDHmi). IDH mutations induce diverse metabolic and epigenetic changes that drive malignant transformation. IDHmi alone are not curative and resistance commonly develops, underscoring the importance of alternate therapeutic options. We were first to report that IDH1/2 mutations induce a homologous recombination (HR) defect, which confers sensitivity to poly (ADP)-ribose polymerase inhibitors (PARPi). Here, we show that the PARPi olaparib is effective against primary patient-derived IDH1/2-mutant AML/ MDS xeno-grafts (PDXs). Olaparib efficiently reduced overall engraftment and leukemia-initiating cell frequency as evident in serial transplantation assays in IDH1/2-mutant but not -wildtype AML/MDS PDXs. Importantly, we show that olaparib is effective in both IDHmi-naïve and -resistant AML PDXs, critical given the high relapse and refractoriness rates to IDHmi. Our pre-clinical studies provide a strong rationale for the translation of PARP inhibition to patients with IDH1/2-mutant AML/ MDS, providing an additional line of therapy for patients who do not respond to or relapse after targeted mutant IDH inhibition.

Advances in non-intensive chemotherapy treatment options for adults diagnosed with acute myeloid leukemia.

Acute myeloid leukemia (AML) is primarily a disease of older adults. Many older patients with AML are not candidates for intensive chemotherapy regimens aimed at inducing remission before transplantation. The prognosis for this patient population remains poor, with 5-year overall survival (OS) rates of less than 10 %. At present, there is no standard of care, and clinical trials should be considered. Hypomethylating agents often are the mainstay of treatment in this setting; however, improved genetic profiling and risk stratification based on molecular, biological, and clinical characteristics of AML enhance the ability to identify an individual patient's risk and can refine therapeutic options. Over the past 2 years, several novel agents have been approved for AML patients in either the frontline or relapsed settings. Additional agents have also shown promising activity. It is becoming a challenge for physicians to navigate these different options and select the optimal therapy or combination of therapies. The aim of this review is to summarize the available information to assist with treatment decisions for leukemia patients who are not suitable for intensive chemotherapy.

Hypomethylating agent based combinations in higher risk myelodysplastic syndrome.

For over a decade the hypomethylating agents (HMA) azacitidine and decitabine have been the mainstay of therapy for myelodysplastic syndrome (MDS). There is a critical need to improve frontline therapy, given that only up to half of high-risk MDS patients will respond to HMA therapy, and responses are short-lived. Currently, a key strategy has been to combine HMAs with other novel agents to improve patient outcomes. While synergy of agents is the goal of combination therapy, combinations often come at the cost of increased side effects that are often intolerable in this vulnerable population. The purpose of this review is to critically examine clinically relevant HMA combinations and discuss the future of MDS management.

Insights into novel emerging epigenetic drugs in myeloid malignancies.

Epigenetics has been defined as 'a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence' and several epigenetic regulators are recurrently mutated in hematological malignancies. Epigenetic modifications include changes such as DNA methylation, histone modifications and RNA associated gene silencing. Transcriptional regulation, chromosome stability, DNA replication and DNA repair are all controlled by these modifications. Mutations in genes encoding epigenetic modifiers are a frequent occurrence in hematologic malignancies and important in both the initiation and progression of cancer. Epigenetic modifications are also frequently reversible, allowing excellent opportunities for therapeutic intervention. The goal of epigenetic therapies is to reverse epigenetic dysregulation, restore the epigenetic balance, and revert malignant cells to a more normal condition. The role of epigenetic therapies thus far is most established in hematologic malignancies, with several agents already approved by the US Food and Drug Administration. In this review, we discuss pharmacological agents targeting epigenetic regulators.

What are the most promising new agents in myelodysplastic syndromes?

PURPOSE OF REVIEW: Myelodysplastic syndromes (MDS) are a diverse group of clonal disorders of hematopoietic stem or progenitor cells that represent the most common class of acquired bone marrow failure syndromes in adults. Despite significant improvement in the pathologic insight into this group of disorders, therapeutic options remain limited and allogeneic hematopoietic stem-cell transplantation is the only treatment that can induce long-term remission in patients with MDS. The goals of therapy for MDS are based on disease prognostication, with a focus of minimizing transfusion dependence and preserving quality of life in low-risk groups and preventing progression of disease to acute myeloid leukemia in high-risk groups. Given the dearth of approved treatment options, there is a marked need for novel therapies across the board, and there are several novel agents currently in the pipeline. RECENT FINDINGS: Among the promising agents with preclinical and early phase efficacy in higher risk MDS, apoptosis targeting with BCL-2 inhibitors have been a standout. There is also a keen interest in immunotherapy, and targeted agents (genetic, signaling pathways, bispecific antibodies, antibody-drug conjugates, and others described in this review). SUMMARY: In this review, we will highlight some of the promising new agents currently under investigation for the management of MDS.

A little CIN may cost a lot: revisiting aneuploidy and cancer.

Despite over 100 years of study, the role of aneuploidy in cancer remains poorly understood. This review highlights the advances in understanding the causes and consequences of aneuploidy. Recent work has illuminated ways in which aneuploidy could have either tumor-promoting or tumor-suppressing effects, similar to what is known for other forms of genetic instability such as telomere attrition [Maser RS, DePinho RA: Connecting chromosomes, crisis, and cancer. Science 2002, 297:565-569]. We explore the possibility that aneuploidy could be just another type of 'mutation', with potential beneficial and deleterious effects, depending on the chromosomes involved and the specific selective pressures the cells experience. We also discuss the potential therapeutic implications of changes in physiology associated with aneuploidy.

Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes.

Multiple centrosomes in tumor cells create the potential for multipolar divisions that can lead to aneuploidy and cell death. Nevertheless, many cancer cells successfully divide because of mechanisms that suppress multipolar mitoses. A genome-wide RNAi screen in Drosophila S2 cells and a secondary analysis in cancer cells defined mechanisms that suppress multipolar mitoses. In addition to proteins that organize microtubules at the spindle poles, we identified novel roles for the spindle assembly checkpoint, cortical actin cytoskeleton, and cell adhesion. Using live cell imaging and fibronectin micropatterns, we found that interphase cell shape and adhesion pattern can determine the success of the subsequent mitosis in cells with extra centrosomes. These findings may identify cancer-selective therapeutic targets: HSET, a normally nonessential kinesin motor, was essential for the viability of certain extra centrosome-containing cancer cells. Thus, morphological features of cancer cells can be linked to unique genetic requirements for survival.