IntroductionThe myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders exhibiting ineffective hematopoiesis characterized by peripheral blood cytopenias. Whole chromosome 5 loss or interstitial deletions spanning 1 copy of 5q31.2 are among the most common abnormalities detected by conventional cytogenetic analysis in de novo (6%-20% of patients) and therapyrelated MDS (up to 40% of patients). [1][2][3] The commonly deleted segment in 5q31.2 has been mapped, 4,5 and mutational analysis of the residual nondeleted allele has not identified a classic tumorsuppressor gene. [4][5][6] Therefore, we and others hypothesize that haploinsufficiency of a gene(s) in 5q31.2, not the loss of both alleles, may be a critical initiating event in MDS pathogenesis and may contribute to acute myeloid leukemia (AML) transformation when combined with additional cooperating mutations.The minimally deleted region on chromosome 5q31.2 is distinct from the minimally deleted region on 5q33.1, 7 which is associated with the 5q minus syndrome and carries a lower risk of progressing to AML compared with 5q31.2 deletions. Haploinsufficiency of the RPS14 gene, located in the 5q33.1 region, causes abnormal erythroid differentiation and accelerated apoptosis both in vitro and in a murine knockout model, supporting its role in the pathogenesis of the 5q minus syndrome. 8,9 Deletions on the long arm of chromosome 5 typically encompass both 5q31.2 and 5q33.1 minimally deleted regions, suggesting that haploinsufficiency of multiple genes may be necessary to recapitulate the full spectrum of abnormalities observed in patients with MDS. Haploinsufficiency of Egr1 (located on 5q31.2), Apc (located proximal to the 5q31.2 minimally deleted region), or Npm (located distal to the 5q31.2 minimally deleted region) are associated with abnormal hematopoiesis in mice, further supporting the possibility that the deletion of multiple 5q genes may cooperate in MDS initiation or progression. [10][11][12][13][14] We hypothesized that haploinsufficiency of HSPA9, a gene located on the 5q31.2 interval, may also influence hematopoiesis in MDS patients based on several observations. HSPA9 mRNA levels are reduced by 50% in CD34 ϩ -purified hematopoietic progenitors isolated from patients with del(5q) MDS compared with MDS patients without del(5q) and normal control CD34 ϩ cells, consistent with haploinsufficient expression levels in del(5q) patients. 6 An N-ethyl-N-nitrosourea mutagenesis screen in zebrafish identified that a bi-allelic mutation in Hspa9 resulted in anemia, dysplastic immature erythroblasts, accelerated apoptosis, and leukopenia. 15 Heterozygous Hspa9 mutant fish also displayed accelerated apoptosis in erythroid cells consistent with ineffective hematopoiesis. 15 In mice, Hspa9 is a gene in the 5q31.2 interval that is a common retroviral insertional mutagenesis site associated with development of AML (see the Mouse Retrovirus Tagged Cancer Gene Database at: http://rtcgd.ncifcrf.gov/). 16 Finally, HSPA9 was identified as a mediator o...

Deletions spanning chromosome 5q31.2 are among the most common recurring cytogenetic abnormalities detectable in myelodysplastic syndromes (MDS). Prior genomic studies have suggested that haploinsufficiency of multiple 5q31.2 genes may contribute to MDS pathogenesis. However, this hypothesis has never been formally tested. Therefore, we designed this study to systematically and comprehensively evaluate all 28 chromosome 5q31.2 genes and directly test whether haploinsufficiency of a single 5q31.2 gene may result from a heterozygous nucleotide mutation or microdeletion. We selected paired tumor (bone marrow) and germline (skin) DNA samples from 46 de novo MDS patients (37 without a cytogenetic 5q31.2 deletion) and performed total exonic gene resequencing (479 amplicons) and array comparative genomic hybridization (CGH). We found no somatic nucleotide changes in the 46 MDS samples, and no cytogenetically silent 5q31.2 deletions in 20/20 samples analyzed by array CGH. Twelve novel single nucleotide polymorphisms were discovered. The mRNA levels of 7 genes in the commonly deleted interval were reduced by 50% in CD34+ cells from del(5q) MDS samples, and no gene showed complete loss of expression. Taken together, these data show that small deletions and/or point mutations in individual 5q31.2 genes are not common events in MDS, and implicate haploinsufficiency of multiple genes as the relevant genetic consequence of this common deletion.

Approximately half of the patients with polycythemia vera experience substantial symptom burdens. We analyzed data from the ongoing Prospective Observational Study of Patients with Polycythemia Vera in US Clinical Practices (REVEAL) study to evaluate the relationship between blood count control and symptoms. The severity of individual symptoms, except for pruritus and night sweats, was not affected by blood count control. Consequently, regular monitoring of symptom burden should be factored when assessing disease control. Background: Approximately 50% of patients with polycythemia vera (PV) have PV-related symptoms at diagnosis; these symptoms might develop or worsen with time. Symptoms have been shown to negatively affect quality of life and interfere with daily activities. To our knowledge, an analysis to evaluate the relationship between blood count control and symptoms has not been published. Patients and Methods: The Prospective Observational Study of Patients with Polycythemia Vera in US Clinical Practices (REVEAL; NCT02252159) is a multicenter, noninterventional, nonrandomized prospective observational study of patients with PV in the United States. Patients included were required to have a complete blood count result within 30 days before completing the at-enrollment Myeloproliferative Neoplasm Self-Assessment Form Total Symptom Score (MPN-SAF TSS). Symptom severity was compared between those who had blood count control versus those who did not. Results: At the time of enrollment, 1714 patients (94.5%) were being managed with cytoreductive therapy; 468 patients (25.8%) had complete hematologic remission (CHR), 1614 patients (89.0%) had !1 controlled blood count, and 1122 patients (61.9%) had !2 controlled blood counts. Mean MPN-SAF TSSs were similar across patients in different blood count control groups. Fatigue was the most frequently reported symptom. The severity of individual symptoms, except those of pruritus and night sweats, was not affected by CHR or the number of blood counts that were controlled. Conclusion: Symptom burden in patients with PV can persist despite control of blood counts, which suggests some discordance between laboratory values and symptom burden. Consequently, regular monitoring of symptom burden should be factored into the assessment of disease control.

National guidelines support the use of hydroxyurea (HU) in high-risk patients with polycythemia vera (PV). In this study, we investigated HU treatment patterns in patients with PV. Of patients who received HU for ‡ 3 months, 32.3% had dose adjustments, 23.7% had dose interruptions, and 18.6% discontinued HU. These results emphasize the need for active management of patients with PV. Background: Polycythemia vera (PV) is associated with increased blood cell counts, risk of thrombosis, and symptoms including fatigue and pruritus. National guidelines support the use of hydroxyurea (HU) in high-risk patients or those with some other clinical indication for cytoreduction. Patients and Methods: REVEAL is a prospective, observational study designed to collect data pertaining to demographics, disease burden, clinical management, patient-reported outcomes, and health care resource utilization of patients with PV in the United States. In this analysis, HU treatment patterns and outcomes were assessed from 6 months prior to enrollment to the time of discontinuation, death, or data cutoff. Results: Of the 1381 patients who received HU for ! 3 months, the median HU exposure was 23.6 months (range, 3.1-38.5 months). The most common maximum daily HU doses were 1000 mg (30.6%) and 500 mg (30.1%); only 6.4% received ! 2 g/d HU. Approximately one-third (32.3%) of patients had dose adjustments, 23.8% had dose interruptions, and 257 (18.6%) discontinued HU. The most common reasons for HU discontinuations and interruptions were adverse events/intolerance (37.1% and 54.5%, respectively) and lack of efficacy (35.5% and 22.1%, respectively). Of those who received HU for ! 3 months, 57.1% had hematocrit values > 45% on ! 1 occasion, 33.1% continued to receive phlebotomies, and 27.4% had uncontrolled myeloproliferation. Conclusion:The results of this analysis emphasize the need for active management of patients with PV with appropriate HU dose titration to maintain blood count control while monitoring for signs and symptoms of HU intolerance.

Donor cell derived malignancies are a rare and interesting complication of allogeneic bone marrow transplantation. We present a case of a 56-year-old male with donor cell myeloid sarcoma of the stomach and myocardium.