Ketterling, Rhett P

Cytogenetic classification by the revised international prognostic scoring system (IPSS‐R) and the prognostic value of monosomal karyotype (MK) were assessed in 783 patients with primary myelodysplastic syndromes (MDS). At 22 months median follow‐up, 562 (72%) deaths were recorded. Percentages of patients with IPSS‐R “very good,” “good,” “intermediate,” “poor,” and “very poor” cytogenetic categories was 5, 63, 18, 4, and 10%, respectively. The corresponding median survivals were 21, 40, 24, 18, and 6.5 months and the inter‐group differences (good vs. very good/intermediate/poor vs. very poor; P < 0.01) or similarities (very good vs. intermediate vs. poor; P = 0.79) were not significantly modified in multivariable analysis. Results were similar when analysis was restricted to 602 patients managed by supportive care. MK adversely affected survival in both poor and very poor karyotype groups (P < 0.01). In conclusion, we were unable to confirm the prognostic superiority of IPSS‐R‐very good karyotype or prognostically distinguish between very good, intermediate and poor karyotypes. Furthermore, we show additional prognostic information from MK in poor/very poor karyotype. Am. J. Hematol. 88:690–693, 2013. © 2013 Wiley Periodicals, Inc.

AbstractWe previously reported an increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first‐degree relatives of MGUS and multiple myeloma patients. Here, we examine whether primary cytogenetic categories of myeloma differ between patients with and without a family history of MGUS or myeloma. We studied 201 myeloma patients with available data on family history and molecular cytogenetic classification. Myeloma with trisomies was more common in probands who had an affected first‐degree relative with MGUS or myeloma compared with those without a family history (46.9% vs. 33.5%, P = 0.125); however, the difference was not statistically significant. Additional studies on the cytogenetic types of myeloma associated with familial tendency are needed.

Generalized eruptive histiocytosis, described in 1963 by Winklemann and Muller, is a reactive, self‐healing form of non‐Langerhans histiocytosis. Rare cases of atypical generalized eruptive histiocytosis have been reported in patients with hematopoietic malignancy, but the biological relationship between the two disorders is not known. We report an 84‐year‐old man with chronic myelomonocytic leukemia who presented with coalescing erythematous papules and plaques on the posterior neck, ear and lower lip, followed by development of blast crisis. Skin biopsy revealed a thick band‐like dermal infiltrate of cells that exhibited morphologic features of macrophages or histiocytes and prominent elastolytic phagocytosis. These cells demonstrated a mature immunophenotype, expressing CD14 and CD68, with partial expression of CD13 but not CD1a, CD43, CD56, CD123, Langerin, or S‐100 protein. Karyotype and fluorescence in situ hybridization analyses showed loss of the Y chromosome in bone marrow and skin specimens, providing evidence of a clonal relationship between the cutaneous eruption and the underlying chronic myelomonocytic leukemia. The presence of the same clone in skin and bone marrow specimens from our patient supports the possibility that atypical generalized eruptive histiocytosis is a marker for underlying hematopoietic malignancy. Discovery of additional cases may shed further light on the pathogenesis of this rare entity.

SRSF2, SF3B1, and U2AF35 (U2AF1) are the three most frequent genes involved with spliceosome mutations in myeloid malignancies. SF3B1 mutations are most frequent (~80%) in myelodysplastic syndromes (MDS) with ring sideroblasts (RS) but lack prognostic relevance. SRSF2 mutations are associated with shortened overall (OS) and leukemia‐free survival (LFS) in both MDS and myelofibrosis. In this study of 226 patients with chronic myelomonocytic leukemia (CMML), mutational frequencies were 40% for SRSF2 (all affecting P95), 6% for SF3B1 (primarily K700E) and 9% for U2AF35 (mostly S34F and Q157P/R). These mutations were mutually exclusive and 54% of the patients displayed at least one mutation. The three mutation groups were phenotypically similar, with the exception of higher RS% (P < 0.0001) in patients with SF3B1 mutations. At a median follow‐up of 15 months, 176 (78%) deaths and 32 (14%) leukemic transformations were documented. OS (median survivals of 17, 16, 17, and 20 months; P = 0.48) and LFS (leukemic transformation rates of 17, 13, 15, and 5%; P = 0.63) were similar among patients with none of the three mutations, SRSF2, SF3B1, or U2AF35 mutations, respectively. We conclude that SRSF2 is the most frequently mutated spliceosome gene in CMML but neither it nor SF3B1 or U2AF35 mutations are prognostically relevant. Am. J. Hematol. 88:201–206, 2013. © 2012 Wiley Periodicals, Inc.

Abstract Genetic lesions such as BCR–ABL1, E2A–PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR–ABL1-positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR–ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALLs. In E2A–PBX1-positive B-ALLs, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A–PBX1 chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), suggesting that E2A–PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLLr B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLLr leukemia cells, suggesting BCL6-targeted therapy as a new therapeutic strategy for MLLr B-ALLs. Significance: We conducted the first integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This study links for the first time the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation mediated by cytosine methylation. We identify a novel clinically actionable biomarker in B-ALLs: IL2RA(CD25), which is linked with BCR–ABL1 and an inflammatory signaling network associated with chemotherapy resistance. We show that BCL6 is a novel MLL fusion protein target that is required to maintain the proliferation and survival of primary human adult MLLr cells and provide the basis for a clinical trial with BCL6 inhibitors for patients with MLLr. Cancer Discov; 2(11); 1004–23. ©2012 AACR. Read the Commentary on this article by Cimmino and Aifantis, p. 976. This article is highlighted in the In This Issue feature, p. 961

Abstract Among spliceosome component mutations, those involving SF3B1 are most frequent in myelodysplastic syndromes with ring sideroblasts (MDS-RS; ∼ 75% incidence) and SRSF2 in chronic myelomonocytic leukemia (∼ 28% incidence). We recently reported on the lack of prognostic significance for SF3B1 mutations in both MDS-RS and primary myelofibrosis (PMF). In the current study, we examined the prevalence and prognostic relevance of SRSF2 mutations in PMF. Among 187 patients screened, 32 (17%) harbored SRSF2 monoallelic mutations affecting residue P95. Significant associations were demonstrated between SRSF2 mutations and advanced age (P < .01), IDH mutations (P < .01), and higher DIPSS-plus risk category (P = .03). SRSF2 mutations were associated with shortened overall (P < .01) and leukemia-free (P < .01) survival; the adverse effect on survival was independent of DIPSS-plus (P = .01; HR = 1.9; 95% CI, 1.1-3.0) and IDH mutations (P < .01; HR = 2.3; 95% CI, 1.4-3.8). In conclusion, SRSF2 mutations are relatively common in PMF, cluster with IDH mutations, and are independently predictive of poor outcome.

Abstract We determined the prognostic relevance of CD25 (IL-2 receptor-α) expression in 657 patients (≤ 60 years) with de novo acute myeloid leukemia (AML) treated in the Eastern Cooperative Oncology Group trial, E1900. We identified CD25POS myeloblasts in 87 patients (13%), of whom 92% had intermediate-risk cytogenetics. CD25 expression correlated with expression of stem cell antigen CD123. In multivariate analysis, controlled for prognostic baseline characteristics and daunorubicin dose, CD25POS patients had inferior complete remission rates (P = .0005) and overall survival (P < .0001) compared with CD25NEG cases. In a subset of 396 patients, we integrated CD25 expression with somatic mutation status to determine whether CD25 impacted outcome independent of prognostic mutations. CD25 was positively correlated with internal tandem duplications in FLT3 (FLT3-ITD), DNMT3A, and NPM1 mutations. The adverse prognostic impact of FLT3-ITDPOS AML was restricted to CD25POS patients. CD25 expression improved AML prognostication independent of integrated, cytogenetic and mutational data, such that it reallocated 11% of patients with intermediate-risk disease to the unfavorable-risk group. Gene expression analysis revealed that CD25POS status correlated with the expression of previously reported leukemia stem cell signatures. We conclude that CD25POS status provides prognostic relevance in AML independent of known biomarkers and is correlated with stem cell gene-expression signatures associated with adverse outcome in AML.

Abstract Peripheral T-cell lymphomas (PTCLs) are aggressive malignancies of mature T lymphocytes with 5-year overall survival rates of only ∼ 35%. Improvement in outcomes has been stymied by poor understanding of the genetics and molecular pathogenesis of PTCL, with a resulting paucity of molecular targets for therapy. We developed bioinformatic tools to identify chromosomal rearrangements using genome-wide, next-generation sequencing analysis of mate-pair DNA libraries and applied these tools to 16 PTCL patient tissue samples and 6 PTCL cell lines. Thirteen recurrent abnormalities were identified, of which 5 involved p53-related genes (TP53, TP63, CDKN2A, WWOX, and ANKRD11). Among these abnormalities were novel TP63 rearrangements encoding fusion proteins homologous to ΔNp63, a dominant-negative p63 isoform that inhibits the p53 pathway. TP63 rearrangements were seen in 11 (5.8%) of 190 PTCLs and were associated with inferior overall survival; they also were detected in 2 (1.2%) of 164 diffuse large B-cell lymphomas. As TP53 mutations are rare in PTCL compared with other malignancies, our findings suggest that a constellation of alternate genetic abnormalities may contribute to disruption of p53-associated tumor suppressor function in PTCL.

AbstractMutations in the all-trans retinoic acid (ATRA)–targeted ligand binding domain of PML-RARα (PRα/LBD+) have been implicated in the passive selection of ATRA-resistant acute promyelocytic leukemia clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PRα/LBD+ (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRα/LBD+. Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD+), which were differentially associated with PRα/LBD+ depending on ATRA treatment status at relapse: positively, On-ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PRα/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD+ were negatively associated and were oppositely associated with presenting white blood count and PML-RARα type: ACA, low, L-isoform; FLT3-ITD+, high, S-isoform. These exploratory results suggest that differing PRα/LBD+ activities may interact with FLT3-ITD+ or ACA, that FLT3-ITD+ and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PRα/LBD+ were also associated with reduced postrelapse survival.