Clinical Implications of Clonal Hematopoiesis

Clonal hematopoiesis (CH)—an expansion of blood cells derived from a single hematopoietic stem cell—is a defining feature of hematologic cancers, but recently CH was also found to be a frequent consequence of aging. When aging-associated CH results from acquisition of a somatic mutation in a driver gene associated with leukemia, and this mutation is present at a variant allele frequency of at least 0.02 (2%) yet the patient does not meet World Health Organization diagnostic criteria for a hematologic neoplasm, this state is termed clonal hematopoiesis of indeterminate potential (CHIP). CHIP is present in approximately 10% to 15% of people older than 70 years and more than 30% by age 85 years and represents a precursor state for neoplasia akin to monoclonal gammopathy of undetermined significance. Recently, CHIP was unexpectedly found to be an important risk factor for cardiovascular events, with accumulating evidence supporting a mechanism of accelerated atherogenesis as a result of vascular inflammation driven by clonally derived monocytes/macrophages. Risk factors for CHIP include aging, male sex, cigarette smoking, and a common germline variant in the telomere-associated gene TERT. Clonal hematopoiesis can also occur after cytotoxic chemotherapy or radiotherapy for a solid tumor, after hematopoietic stem cell transplant, in the context of aplastic anemia, or after induction chemotherapy for acute leukemia; in each setting, CH has distinct clinical implications. This review summarizes recent studies of CH and CHIP and outlines challenges in clinical management of affected patients.     

Clinical, haematological and histomorphological profile of adult myelodysplastic syndrome. Study of 96 cases in a single institute

Myelodysplastic syndromes (MDS) are clonal haematopoietic stem cell disorders characterised by ineffective and dyspoietic haematopoiesis. The natural history of these disorders is variable and ranges from a chronic to a rapid course towards leukaemic progression. Certain shortcomings have been encountered in the French-American-British (FAB) classification over the years, and therefore there is a need for an alternative method of classification. In 1999, the WHO published a revised classification of MDS. In the present study, we have analysed the clinical, haematological and histomorphological features in 96 cases of primary MDS seen in the department of haematology at the All India Institute of Medical Sciences (AIIMS) over a 6-yr period (1996-2001). Both FAB and WHO classifications have been incorporated and the Bournemouth scoring system applied in each case at presentation. The Bournemouth scoring system, in the absence of a cytogenetic study, offers a good prognostication and long-term survival estimate.     

Quality of life and brain function following high-dose recombinant human erythropoietin in low-risk myelodysplastic syndromes: a preliminary report

OBJECTIVE: In this prospective study we evaluate the effects of high-dose recombinant human erythropoietin (rHuEPO) on quality of life (QOL) and brain function in patients with low-risk myelodysplastic syndromes (MDS) (<10% marrow blasts). Preliminary data are reported. METHODS: Eleven consecutive patients were given rHuEPO (40,000 IU two times a week) for 12 wk. Responsive patients continued with 40,000 IU/wk for further 12 wk. Changes in QOL were assessed by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) self-report. Neurophysiological evaluation at the start of the therapy (t0) included duplex scanning of neck vessels, transcranial Doppler sonography (TCD), a complex neuropsychological evaluation, and quantitative electroencephalography (qEEG). Eight patients completed the neurophysiological evaluation after 24 wk (t1). RESULTS: Six patients (55%) achieved an erythroid response after 12 wk, which was maintained after 24 wk of treatment. FACT-An score showed a relevant improvement between t0 and t1 in these patients. At baseline, TCD showed a mean cerebral blood flow (CBF) velocity in the upper normal range. Abnormalities in brain function were observed in five patients. In the eight patients who were re-evaluated at t1, improvement was observed in three responding patients, two of them with abnormal values at t0. A strict correlation between QOL and neurophysiological improvements was not observed. CONCLUSIONS: A high-dose induction phase with rHuEPO followed by maintenance therapy may be an effective therapeutic schedule for low-risk MDS patients. The erythroid response was associated with positive changes in the QOL. Neurophysiological improvements occurred only in a part (50%) of responding patients, mainly those who showed altered results at baseline.     

Clofibric acid: a potential therapeutic agent in AML and MDS

Differentiation therapy using retinoic acids (RAs) or 1alpha25-dihydroxyvitamin D3 (D3) is an attractive alternative to chemotherapy in acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). However, with the exception of RA therapy for acute promyelocytic leukaemia (APL), RAs and D3 are not potent enough at doses that can be tolerated by patients. We demonstrate that clofibric acid (CA) enhances the response of HL60 cells to all-trans RA and D3. Our findings and those of others in the field lead us to suggest that combination therapy using all-trans RA and CA should be considered as potential therapy for AML and MDS.     

Mutation inε-Sarcoglycan Induces a Myoclonus-Dystonia Syndrome-Like Movement Disorder in Mice

Myoclonus dystonia syndrome(MDS)is an inherited movement disorder,and most MDS-related mutations have so far been found in theε-sarcoglycan(SGCE)coding gene.By generating SGCE-knockout(KO)and human 237 C>T mutation knock-in(KI)mice,we showed here that both KO and KI mice exerted typical movement defects similar to those of MDS patients.SGCE promoted filopodia development in vitro and inhibited excitatory synapse formation both in vivo and in vitro.Loss of function of SGCE leading to excessive excitatory synapses that may ultimately contribute to MDS pathology.Indeed,using a zebrafish MDS model,we found that among 1700 screened chemical compounds,Vigabatrin was the most potent in readily reversing MDS symptoms of mouse disease models.Our study strengthens the notion that mutations of SGCE lead to MDS and most likely,SGCE functions to brake synaptogenesis in the CNS.