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The outbreak of the novel coronavirus disease (COVID-19) in December 2019 in Wuhan, China, evolved to a deadly pandemic that has resulted in more than 103 million cases worldwide and nearly 2.5 mil...

Thrombocytopenia is a major cause of morbidity and mortality in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) [1]. Ineffective hematopoiesis and infiltration of the...

The emergence of the Coronavirus Disease -19 (COVID-19) pandemic, has had a tremendous global impact, resulting in substantial morbidity and mortality worldwide and especially in the United States, where nearly one third of the cases are located. Although involvement of the lower respiratory track accounts for most of the morbidity and mortality seen, the virus involves several organ systems and the syndrome exhibits clinical diversity with a wide range of symptoms and manifestations. The involvement of elements of the hematopoietic system is prominent in severe cases and associated with poor outcomes and mortality. Lymphopenia, leukopenia, thrombocytopenia, disseminated intravascular coagulation, and a prothrombotic state are common manifestations of COVID-19 and have important treatment and prognostic implications. Better understanding of the mechanisms of the pathophysiology of COVID-19-induced hematological abnormalities may ultimately result in better ways to treat them and decrease the associated morbidity and mortality.

Myosteatosis refers to fat deposition within muscle and is linked to risk of cardiovascular disease and metabolic disorders. Though these comorbidities are common during and after therapy for acute lymphoblastic leukemia (ALL), little is known about tissue distribution, including myosteatosis, in this population. Using quantitative computed tomography, we assessed the impact of ALL therapy on bone, muscle, subcutaneous and muscle-associated (MA) fat in 12 adolescents and young adults (AYA) treated for ALL as compared to a healthy control group without ALL (n=116). AYA had a marked loss of muscle with a gain in MA fat between ALL diagnosis and end of induction. These changes persisted throughout intensive therapy. Lower bone and muscle and higher MA fat were also observed during and after treatment in comparison to controls. Altered lower extremity tissue distribution, specifically myosteatosis and sarcopenia, may contribute to functional declines and increased risk of metabolic disorders and cardiovascular diseases.

The myelodysplastic syndromes (MDS) are a group of myeloid malignancies with diverse presentation, characteristics, and pathological features. A particular area of divergent features in MDS relates...

The mammalian target of rapamycin (mTOR) pathway is a major therapeutic target in the treatment of hematological malignancies, as it controls cellular events of high importance for regulation of mRNA translation and protein production. Rapalogs, or first-generation mTOR inhibitors, have produced only modest clinical benefits so far. Limitations to rapalogs likely result from the partial inhibition of mTORC1 substrates and lack of effects on mTORC2. Efforts toward the development of agents with more potent and complete inhibitory effects on the mTOR pathway have resulted in the development of catalytic mTOR inhibitors. Key preclinical and early clinical investigations of several catalytic mTOR inhibitors and potential resistance mechanisms to their activities are summarized here.

The myelodysplastic syndromes (MDS) represent clonal myeloid disorders with a broad spectrum of clinical course, response to therapy, and overall prognosis. Various prognostic scales exist to risk ...

Statins are HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase inhibitors, which block the conversion of HMG-CoA to mevalonate and have potent cholesterol lowering properties. Beyond their importance in the generation of lipid lowering effects, the regulatory effects of statins on the mevalonate pathway have a significant impact on multiple other cellular functions. There is now extensive evidence that statins have anti-inflammatory and anti-neoplastic properties, but the precise mechanisms by which such responses are generated are not well understood. In the present study we demonstrate that statins engage a member of the protein kinase C (PKC) family of proteins, PKCδ, in acute promyelocytic leukemia (APL) cells. Our study shows that atorvastatin and fluvastatin induce proteolytic activation of PKCδ in the APL NB4 cell line, which expresses the t(15;17) translocation. Such engagement of PKCδ results in induction of its kinase domain and downstream regulation of pathways important for statin-dependent leukemia cell differentiation. Our research shows that the function of PKCδ is essential for statin-induced leukemic cell differentiation, as demonstrated by studies involving selective targeting of PKCδ using siRNAs. We also demonstrate that the potent enhancing effects of statins on all-trans retinoic acid (ATRA)-induced gene expression for CCL3 and CCL4 requires the function of PKCδ, suggesting a mechanism by which statins may promote ATRA-induced antileukemic responses. Altogether, our data establish a novel function for PKCδ as a mediator of statin-induced differentiation of APL cells and antileukemic effects.

The clonal selective pressure of tyrosine kinase inhibitors (TKIs) in the treatment of oncogene-addicted malignancies can result in the emergence of kinase domain ‘gatekeeper’ mutations that confer...

The protein kinase C (PKC) family of proteins includes several kinases that share structural homology, but at the same time exhibit substantial functional diversity. There is a significant amount of evidence establishing distinct patterns of expression and function for different PKC isoforms and groups in different leukemias. Although most members of this family promote leukemic cell survival and growth, others exhibit opposing effects and participate in the generation of antileukemic responses. This review summarizes work in this field on the relevance of distinct members of the PKC family in the pathophysiology of myeloid and lymphoid leukemias. The clinical-therapeutic potential of such ongoing work for the treatment of future development of novel approaches for the treatment of different types of leukemias is discussed.

The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) is one of the greatest success stories in oncology. With long-term follow-up, continued treatment of chronic p...

It is well established that IFNalpha has significant clinical activity in the treatment of chronic myelogenous leukemia (CML). This cytokine has been used for many years in the management of patients in the chronic phase of the disease, but the mechanisms by which it induces growth inhibitory effects in CML-cells have not been elucidated. Understanding the signaling mechanisms by which the Type I IFN receptor transduces growth inhibitory signals in BCR-ABL expressing cells should prove very valuable, as it may result in the design of new, more specific pharmacological compounds that target the same cellular cascades. Recent evidence indicates that, in addition to the classic IFN-activated Jak-Stat pathway, the Type I IFN receptor engages in its signaling cascade the CrkL-adapter protein, which is also a substrate for the kinase activity of the BCR-ABL oncogene. In addition, it appears that activation of a member of the Map kinase (MAPK) family of proteins, the p38 MAPK, is essential for the generation of the antileukemic effects of IFNalpha. This review summarizes the recent advances in the-field of interferon signaling in CML cells and discusses the implications of identifying signaling proteins that mediate IFNalpha-induced growth inhibition.

DAB486IL-2 is a recombinant fusion toxin, created by replacement of the receptor binding domain sequences of the diphtheria toxin gene with the sequences for human interleukin-2 (IL-2). It selectively binds to and intoxicates cells expressing the high-affinity IL-2 receptor. A total of 17 patients with refractory hematologic malignancies were entered in a phase I study of DAB486IL-2, administered as a 6 hour continuous intravenous infusion on days 1, 2, 8, 9, 15, and 16 of each 28 day cycle. Cohorts of 3 to 6 patients were treated with escalating doses. The starting dose was 0.1 mg/kg/day with increments of 0.1 mg/kg/day per dose level up to 0.3 mg/kg/day. Significant adverse effects included transient asymptomatic elevation of liver transaminases, hypersensitivity, anemia, thrombocytopenia, fever, and creatinine elevation. A partial response of approximately nine months duration was observed in a patient with small cell lymphocytic non-Hodgkin's lymphoma, previously refractory to high-dose chemotherapy and autologous bone marrow transplantation. The observance of antitumor activity in a patient highly refractory to chemotherapy suggests that DAB486IL-2 may have efficacy in selected patients whose malignant cells express the IL-2 receptor.

Whether acute myeloid leukemia expressing Philadelphia chromosome (Ph+AML) is a distinct clinicopathologic entity and not the de novo presentation of myeloid blast phase of chronic myeloid leukemia...

Th e introduction in clinical practice of tyrosine kinase inhibitors (TKIs) targeting the oncogenic BCR – ABL protein has had a dramatic impact on the natural history of chronic myeloid leukemia (CML) and, in many cases, has transformed this previously fatal leukemia into a manageable chronic condition. Although in some epidemiological studies the estimated life expectancy of patients with chronic phase CML (CML-CP) receiving TKIs approaches that of the general population, approximately 30% of patients will either fail to respond to imatinib mesylate or will develop secondary resistance, with disease progression after an initial response [1,2]. Th is has necessitated a better understanding of the mechanisms by which leukemia cells develop resistance to TKIs and the design of approaches to identify and, possibly, predict emergence of such resistance. Over the last decade, substantial advances have been made in delineating molecular mechanisms of imatinib resistance in vitro and in vivo . Among them are overexpression of BCR – ABL, mutations in BCR – ABL, activation of alternative survival pathways and alterations in drug effl ux transporters [3 – 5]. However, the presence of a particular mechanism of resistance in leukemic cells does not necessarily establish that such a mechanism operates alone, and it is possible that more than one mechanism and pathways may be involved in the emergence of resistance and clinical progression in a given patient. Because of the continuous emergence of new mechanisms of resistance of BCR – ABL transformed cells, several rationally designed kinase inhibitors are currently in various stages of clinical development. The most advanced third-generation TKI, ponatinib, is active against the T315I-BCR – ABL mutation [6,7]. Beyond BCR – ABL, this TKI also targets and inhibits other kinases, including FLT3 (fms-like tyrosine kinase receptor-3), FGFR (fibroblast growth factor receptor), VEGFR (vascular endothelial growth factor receptor), c-Kit and PDGFR (platelet derived growth factor receptor) [6,7]. Aurora kinase inhibitors such as AT9283 and danusertib are also currently in clinical trials [8], while other inhibitors currently undergoing preclinical or clinical evaluation include the “ switch pocket inhibitor ” DCC-2036 [9] and GNF-2, an allosteric, non-adenosine triphosphate (ATP) competitive BCR – ABL inhibitor, which specifically binds at the myristoyl binding cleft of BCR – ABL [10]. There are also compounds that are believed to exhibit antileukemic effects by causing degradation of BCR – ABL. Among them is PEITIC (phenylethyl isothiocyanate), a natural compound found in vegetables, which exhibits antileukemic effects in vitro via induction of oxidative stress, leading to BCR – ABL degradation [11]. With the emergence of resistance to TKIs, the development of new drugs for the treatment of CML and Philadelphia chromosome positive (Ph ) acute lymphoblastic leukemia (ALL) continues to be relevant and important. In this issue of Leukemia and Lymphoma , Pillai et al . demonstrate that treatment of K562 cells with 8-aminoadenosine results in an increase in 8-amino-ATP, accompanied by a decline in the endogenous ATP pool [12]. Th e authors also demonstrate that 8-amino-adenosine inhibits BCR – ABL mRNA synthesis, suggesting a mechanism by which this agent may generate antileukemic responses, by blocking expression of the BCR – ABL oncoprotein. Such eff ects apparently resulted in increased apoptosis of transformed cells and modest enhancing eff ects on the generation of imatinib mesylate-responses in sensitive cells. Although the results of this study are premature to enable conclusions to be drawn regarding the potential utility of 8-amino-adenosine, the demonstration of suppression of BCR – ABL mRNA expression by this agent is interesting. Such fi ndings raise the possibility of future combinations of agents that suppress BCR – ABL mRNA expression with TKIs or other agents that target key survival pathways in leukemia cells, and this remains to be addressed in further preclinical studies.