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Differentially Expressed Proteins Deleted versus non-deleted clones

Differentially expressed genes in Xenograted T-ALL shSYNCRIP-SNHG5 versus ShCtrl

Differentially translated transcripts - translatome

Supp Fig. S1-6, Supp Tables S1-S3, Supp Methods and References

Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, SYNCRIP (encoding hnRNP-Q) and SNHG5 (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated leukemogeneis in a Tal1/Lmo1/Notch1-driven mouse model, demonstrating the tumor-suppressive nature of the two-gene region. Proteomic and translational profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia-initiating cell activity of primary human leukemic cells upon coextinction of SYNCRIP and SNHG5. Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosomes and mitochondria in T-ALL tumor progression.Significance:The oncogenic role of 6q deletion in T-ALL has remained elusive since this chromosomal abnormality was first identified more than 40 years ago. We combined genomic analysis and functional models to show that the codeletion of two contiguous genes at 6q14 enhances malignancy through deregulation of a ribosome–mitochondria axis, suggesting the potential for therapeutic intervention.This article is highlighted in the In This Issue feature, p. 1494

The mean age at diagnosis of chronic lymphocytic leukemia (CLL) is 72 years, with 22.8% of patients being older than 80 years. However, the elderly are underrepresented in clinical studies of CLL. We performed a retrospective study of CLL patients aged 80 years or older at the initiation of first-line therapy in hospitals affiliated with the French intergroup on CLL (French Innovative Leukemia Organization) between 2003 and 2013. Here, we describe the clinical and biological characteristics, treatment, and outcomes for 201 patients. The median age of the cohort was 83.2 years (80-92 years). The median Cumulative Index Rating Scale comorbidity score was 5 and the median creatinine clearance was 48 mL/min (Cockcroft-Gault formula). At treatment initiation, Binet stage was A (26.4%), B (27.9%), or C (40.3%). Therapy consisted mainly of chlorambucil (65.7%), bendamustine (10.5%), and rituximab (44.3%) as follows: chlorambucil alone (45.3%) or immunochemotherapy (48.3%) with rituximab + chlorambucil (22.7%), rituximab + bendamustine (10.4%), or rituximab + cyclophosphamide + dexamethasone (5.5%). The overall response rate was 66.2% with 31.8% clinical complete remission. The median overall and progression-free survival from treatment initiation was 53.7 and 18.3 months, respectively. These results suggest that treatment is feasible in this age group, even with immunochemotherapy. Thus, prospective trials should target this population and oncogeriatric evaluation and new targeted therapies should be part of such future trials.

Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, SYNCRIP (encoding hnRNP-Q) and SNHG5 (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated leukemogeneis in a Tal1/Lmo1/Notch1-driven mouse model, demonstrating the tumor-suppressive nature of the two-gene region. Proteomic and translational profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia-initiating cell activity of primary human leukemic cells upon coextinction of SYNCRIP and SNHG5. Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosomes and mitochondria in T-ALL tumor progression. Significance: The oncogenic role of 6q deletion in T-ALL has remained elusive since this chromosomal abnormality was first identified more than 40 years ago. We combined genomic analysis and functional models to show that the codeletion of two contiguous genes at 6q14 enhances malignancy through deregulation of a ribosome–mitochondria axis, suggesting the potential for therapeutic intervention. This article is highlighted in the In This Issue feature, p. 1494

The mean age at diagnosis of chronic lymphocytic leukemia (CLL) is 72 years, with 22.8% of patients being older than 80 years. However, the elderly are underrepresented in clinical studies of CLL. We performed a retrospective study of CLL patients aged 80 years or older at the initiation of first-line therapy in hospitals affiliated with the French intergroup on CLL (French Innovative Leukemia Organization) between 2003 and 2013. Here, we describe the clinical and biological characteristics, treatment, and outcomes for 201 patients. The median age of the cohort was 83.2 years (80-92 years). The median Cumulative Index Rating Scale comorbidity score was 5 and the median creatinine clearance was 48 mL/min (Cockcroft-Gault formula). At treatment initiation, Binet stage was A (26.4%), B (27.9%), or C (40.3%). Therapy consisted mainly of chlorambucil (65.7%), bendamustine (10.5%), and rituximab (44.3%) as follows: chlorambucil alone (45.3%) or immunochemotherapy (48.3%) with rituximab + chlorambucil (22.7%), rituximab + bendamustine (10.4%), or rituximab + cyclophosphamide + dexamethasone (5.5%). The overall response rate was 66.2% with 31.8% clinical complete remission. The median overall and progression-free survival from treatment initiation was 53.7 and 18.3 months, respectively. These results suggest that treatment is feasible in this age group, even with immunochemotherapy. Thus, prospective trials should target this population and oncogeriatric evaluation and new targeted therapies should be part of such future trials.

Cancer cells require glutamine to adapt to increased biosynthetic activity. The limiting step in intracellular glutamine catabolism involves its conversion to glutamate by glutaminase (GA). Different GA isoforms are encoded by the genes GLS1 and GLS2 in humans. Herein, we show that glutamine levels control mitochondrial oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) cells. Glutaminase C (GAC) is the GA isoform that is most abundantly expressed in AML. Both knockdown of GLS1 expression and pharmacologic GLS1 inhibition by the drug CB-839 can reduce OXPHOS, leading to leukemic cell proliferation arrest and apoptosis without causing cytotoxic activity against normal human CD34(+) progenitors. Strikingly, GLS1 knockdown dramatically inhibited AML development in NSG mice. The antileukemic activity of CB-839 was abrogated by both the expression of a hyperactive GAC(K320A) allele and the addition of the tricarboxyclic acid cycle product α-ketoglutarate, indicating the critical function of GLS1 in AML cell survival. Finally, glutaminolysis inhibition activated mitochondrial apoptosis and synergistically sensitized leukemic cells to priming with the BCL-2 inhibitor ABT-199. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy for AML.

Introduction: Median age of Chronic Lymphocytic Leukemia (CLL) patients is 72 years with 40% older than 75 and 22.8% over 80 years. Important therapeutic progresses have been made, including chemo-immunotherapy as well as the recent use of targeted therapies, leading to progression-free-survival (PFS) and overall survival (OS) improvements. Although the elderly represents the largest subgroup of CLL patients, they are underrepresented in clinical studies and little is known about their clinical characteristics, treatment and outcome. Consequently, results from trials cannot be directly translated into clinical practice for these patients. Bairey et al (Ann Hematol, 2011) reported a series of 214 patients (80 years or older) diagnosed in Israel between 1979 and 2009 with a mean age of 84. However, in this cohort, 56% of the patients had a Rai stage 0 and only 53 received treatment. Median survival was 56 months. Methods: We performed a retrospective study of CLL patients aged 80 or more at initiation of first line therapy. Patients were treated between 2003 and 2013, in 17 hospitals affiliated to the French Innovative Leukemia Organisation (FILO). We report here a cohort of 201 such CLL patients, and describe their clinical and biological characteristics, treatment options and outcome. Results: Patients' median age was 83.4 years (80-92), 29% were older than 85 years, and the sex ratio was 60% male/40% female. Performance status (97%≤ 2) and nutritional status (median Corporal Mass Index of 25.3 kg/m²) were preserved. The median Cumulative Index Rating Scale (CIRS) comorbidity score was 5. More precisely in term of fitness, 57.8% patients were characterized as "go-go" with a CIRS ≤ 6 and organ comorbidities Diagnosis relied on a Royal Marsden Hospital (RMH) score > 3, and CD38 was positive in 43,4% of the 129 cases tested (64%). Cytogenetic data were available for 42% of the patients. Isolated abnormalities were deletion 13q (38.1%), trisomy 12 (21.4%), deletion 17q (10.7%) or deletion 11q (7.1%). Besides, associated chromosomic abnormalities were detected, mainly by fluorescence in situ hybridization (FISH) and complex karyotypes (1.2%). At treatment initiation, Binet stage was either A (27.2%), B (28.7%) or C (41.5%). Therapies consisted mainly in Chlorambucil (65.5%), Bendamustine (10.5%) and Rituximab (44.3%). Indeed, therapy regimens were composed of Chlorambucil alone (45.3%) or chemo-immunotherapy (48.3%) including Rituximab+Chlorambucil (22.7%), Rituximab+Bendamustine (10.4%), Rituximab+Cyclophosphamide+Dexamethasone (5.5%) or Rituximab+Fludarabine+Cyclophosphamide (5.5%). In term of tolerance, 20.2% of the patients required hospitalization and 10% of these cases were febrile neutropenia. Finally, 31.8% required a dose reduction of chemotherapy. The Overall Response Rate was 65.9% with 31.4% of clinical complete remission. The median OS and PFS (from treatment initiation) were 48.6 and 18 months, respectively (cf. Survival curves). Afterwards, an important number of patients (41.3%) remained fit enough to receive a second line treatment. In univariate analysis, only comorbidities evaluated by the CIRS had a significant impact on survival (p=0.03). Indeed patients identified as fit by a CIRS score ≤ 6 and no organ comorbidity > 3 had a better outcome. Conclusion: We report a large series of elderly CLL patients, who received first line treatment at a median age of 83. Median OS was about 4 years, which is less than normal population of the same age. Our results suggest that treatment (including immunochemotherapy) is feasible, even in this very old population. Different bias are possible in this retrospective study including the selection of only fit patients, the low percentage of geriatric evaluation, and the possible undertreatment of this population since chlorambucil was the most frequent treatment. In the future, prospective trials should target this population. Oncogeriatric evaluation and new targeted therapies should be part of such future trials. Figure 1. Survival curve 1: Overall Survival Figure 1. Survival curve 1: Overall Survival Figure 2. Survival curve 2: Progression Free Survival Figure 2. Survival curve 2: Progression Free Survival Disclosures Dupuis: ROCHE: Speakers Bureau; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Aurran-Schleinitz:CSLBehring: Honoraria; Janssen: Honoraria. Cymbalista:Karyopharm: Honoraria; Gilead: Honoraria; Roche: Honoraria; Janssen: Honoraria, Research Funding. Dilhuydy:Roche: Honoraria, Other: Travel reimbursement; Janssen: Honoraria, Other: Travel reimbursement; Mundipharma: Honoraria. Cazin:GILEAD,: Honoraria; ROCHE: Consultancy; MUNDIPHARMA: Honoraria, Research Funding; NOVARTIS: Honoraria. Leblond:Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Mundipharma: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Cartron:Sanofi: Honoraria; Gilead: Honoraria; Celgene: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria.