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Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. The chronic myeloid leukemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph1+: t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival dramatically. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined when BCR-ABL transcripts become undetectable in blood cells3. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukemia stem cells (LCSs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor gamma (PPARg). We found that activation of PPARg by the glitazones decreases expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of CML LSC's quiescence and stemness. When pioglitazone was temporarily given to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool. Disclosures: No relevant conflicts of interest to declare.

Infection of primates by HIV-1 and SIV induces multiple hematological abnormalities of central hematopoietic origin. Although these defects greatly contribute to the pathophysiology of HIV-1 infection, the molecular basis for altered BM function remains unknown. Here we show that when cynomolgus macaques were infected with SIV, the multipotent potential of their hematopoietic progenitor cells was lost, and this correlated with down regulation of STAT5A and STAT5B expression. However, forced expression of STAT5B entirely rescued the multipotent potential of the hematopoietic progenitor cells. In addition, an accessory viral protein required for efficient SIV and HIV replication and pathogenicity, “Negative factor” (Nef), was essential for

Purpose More than half of patients with chronic phase chronic myelogenous leukemia (CP-CML) in complete molecular response (CMR) experience molecular relapse after imatinib discontinuation. We investigated loss of major molecular response (MMR) as a criterion for resuming therapy. Patients and methods A multicenter observational study (A-STIM, According to STop IMatinib) evaluating MMR persistence was conducted in 80 CP-CML patients who had stopped imatinib after prolonged confirmed CMR (24 months or more). Patients with confirmed CMR with 1 or 2 occasional weak positive samples before study entry were also considered eligible. CMR was defined as undetectable BCR-ABL transcript with a sensitivity of at least 40000 amplified copies of the ABL control gene, in accordance with the level of sensitivity routinely applied within laboratories participating in the French GBMHM Network. Results Median time from imatinib initiation to discontinuation was 79 months (range 30-145), median duration of CMR before imatinib discontinuation was 41 months (24-96), and median follow-up after discontinuation was 31 months (8-92). Twenty-nine patients (36%) lost MMR after a median of 4 months off-therapy (2-17). Cumulative incidence of MMR loss was estimated as 35% (95% CI, 25%-46%) at 12 months and 36% (95% CI, 26%-47%) at 24 months whereas probability of losing CMR was estimated as 51% at 12 months (95% CI, 41%-63%) and 54% at 24 months (95% CI, 44%-66%). Fivety two percent of the patients met the criteria for cCMR but experienced occasional BCR-ABL positivity (unstable cCMR). Those patients were not at higher risk of losing MMR as compared to patients with stable cCMR. This observation may potentially increase by two-fold the number of patients eligible for TKI discontinuation. Fluctuation of BCR-ABLtranscript levels below the MMR threshold (≥ 2 consecutive positive values) were observed in 31% of patients after imatinib discontinuation. Using cell sorting in three fluctuating patients, we were able to confirm that BCR-ABL signal was mostly present in the CD15 positive fraction, demonstrating first that BCR-ABL residual signal was not related to long living lymphoid cells and second that residual CML cells retain a clonogenic potential. Treatment-free remission was estimated as 64% (95% CI, 54%-75%) at 12 and 24 months and 61% (95% CI, 51%-73%) at 36 months. Treatment was resumed in 31 patients after loss of MMR. Twenty-three patients regained CMR4.5 and 8 patients are in MMR under therapy after 2+ to 17+ months. Median to time to a second CMR was estimated as 7.3 months in retreated patients. Conclusion The probability of losing MMR after imatinib discontinuation was estimated as 36% in the long-term. Loss of MMR is a practical and safe criterion for restarting therapy in CML patients with prolonged CMR and could be used for future discontinuation studies. Disclosures: Rousselot: Novartis: Research Funding; BMS: Research Funding. Cony-Makhoul:BMS: Honoraria; Novartis: Research Funding. Nicolini:BMS, Teva, Ariad, Pfizer, Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Etienne:Novartis: Consultancy; Pfeizer: Consultancy; Novartis: Honoraria; BMS: Honoraria. Guerci-Bresler:Novartis: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees. Turhan:BMS: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; BMS: Honoraria; Novartis: Research Funding. Guilhot:BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; BMS: Research Funding; Novartis: Research Funding. Mahon:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Brisol Myers Squibb: Consultancy, Honoraria; Ariad: Honoraria; Pfizer: Honoraria.