Identifying precise targets of individual cancers remains challenging. Chronic lymphocytic leukemia (CLL) represents the most common adult hematologic malignancy, and trisomy 12 (tri12) represents a quarter of CLL patients. We report that tri12 human pluripotent stem cells (hPSCs) allow for the identification of gene networks and targets specific to tri12, which are controlled by comparative normal PSCs. Identified targets are upregulated in tri12 leukemic cells from a cohort of 159 patients with monoclonal B cell lymphocytosis and CLL. tri12 signaling patterns significantly influence progression-free survival. Actionable targets are identified using high-content drug testing and functionally validated in an additional 44 CLL patient samples. Using xenograft models, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor is potent and selective against human tri12 CLL versus healthy patient-derived xenografts. Our study uses hPSCs to uncover targets from genetic aberrations and apply them to cancer. These findings provide immediate translational potential as biomarkers and targets for therapeutic intervention.
Apoptosis inducing factor (AIF) is a novel apoptotic effector protein that induces chromatin condensation and large-scale ( approximately 50 kbp) DNA fragmentation when added to purified nuclei in vitro. Confocal and electron microscopy reveal that, in normal cells, AIF is strictly confined to mitochondria and thus colocalizes with heat shock protein 60 (hsp60). On induction of apoptosis by staurosporin, c-Myc, etoposide, or ceramide, AIF (but not hsp60) translocates to the nucleus. This suggests that only the outer mitochondrial membrane (which retains AIF in the intermembrane space) but not the inner membrane (which retains hsp60 in the matrix) becomes protein permeable. The mitochondrio-nuclear redistribution of AIF is prevented by a Bcl-2 protein specifically targeted to mitochondrial membranes. The pan-caspase inhibitor Z-VAD. fmk does not prevent the staurosporin-induced translocation of AIF, although it does inhibit oligonucleosomal DNA fragmentation and arrests chromatin condensation at an early stage. ATP depletion is sufficient to cause AIF translocation to the nucleus, and this phenomenon is accelerated by the apoptosis inducer staurosporin. However, in conditions in which both glycolytic and respiratory ATP generation is inhibited, cells fail to manifest any sign of chromatin condensation and advanced DNA fragmentation, thus manifesting a 'necrotic' phenotype. Both in the presence of Z-VAD. fmk and in conditions of ATP depletion, AIF translocation correlates with the appearance of large-scale DNA fragmentation. Altogether, these data are compatible with the hypothesis that AIF is a caspase-independent mitochondrial death effector responsible for partial chromatinolysis.
Patients over age 60 comprise the majority of those diagnosed with acute myeloid leukemia (AML), but treatment approaches in this population are variable, with many uncertainties and controversies. Our group conducted a literature review to summarize the latest information and to develop a consensus document with practical treatment recommendations. We addressed five key questions: selection criteria for patients to receive intensive induction chemotherapy; optimal induction and post-remission regimens; allogeneic hematopoietic stem cell transplantation (HSCT); treatment of patients not suitable for induction chemotherapy; and treatment of patients with prior hematological disorders or therapy-related AML. Relevant literature was identified through a PubMed search of publications from 1991 to 2012. Key findings included the recognition that cytogenetics and molecular markers are major biologic determinants of treatment outcomes in the older population, both during induction therapy and following HSCT. Although disease-specific and patient-specific risk factors for poor outcomes are more common in the older population, age is not in itself sufficient grounds for withholding established treatments, including induction and consolidation chemotherapy. The role of HSCT and use of hypomethylating agents are discussed. Finally, suggested treatment algorithms are outlined, based on these recommendations.
7025 Background: With 24 mo f/u, ENESTcmr demonstrated higher rates of stable, deep MRs with nilotinib (NIL) vs IM in pts on long-term (≥ 2 y) IM with residual disease. Here, we present 36-mo results, including crossover from IM to NIL after 2 y on study. Methods: Pts with Philadelphia chromosome–positive CML-CP (N = 207) with complete cytogenetic response but detectable BCR-ABL (by RQ-PCR with a sensitivity of ≥ 4.5 logs) after ≥ 2 y on IM were randomized to NIL 400 mg twice daily (BID; n = 104) or IM 400 or 600 mg once daily (QD; n = 103). Crossover from IM to NIL was allowed for pts with detectable BCR-ABL after 24 mo, treatment failure, or confirmed (≥ 2 consecutive assessments) loss of response at any time. Results: Significantly more pts achieved MR4.5 by 36 mo with NIL (Table). Median time to MR4.5 was 24 mo in the NIL arm and not reached in the IM arm with 36 mo f/u. 46 of 103 (45%) pts randomized to IM crossed over to NIL. When accounting only for responses up to crossover, 47% and 24% of pts on NIL and IM, respectively, achieved MR4.5 (P = .0003). At 24 mo, 52 pts on NIL and 78 pts on IM had detectable disease; 4/52 who continued NIL, 0/35 who continued IM, and 11/43 who crossed over from IM to NIL achieved undetectable BCR-ABL by 36 mo. The rate of MR4.5 appeared higher in pts randomized to NIL (33% by 1 y in pts without MR4.5 at baseline [BL]) than in pts who crossed over to NIL (21%) with similar follow-up. Adverse event profile was similar to the 12 mo report. Conclusions: By 36 mo, significantly more pts achieved MR4.5 by switching to NIL vs remaining on IM and median time to MR4.5 was accelerated by more than 1 y in the NIL arm. Pts with detectable disease who crossed over from IM to NIL after 24 mo were able to achieve deep MRs by 36 mo on study, whereas no pts who remained on IM achieved undetectable BCR-ABL. Delaying switching from IM to the more potent BCR-ABL inhibitor NIL does not increase the proportion of pts achieving deep MR. Clinical trial information: CAMN107A2405. NIL 400 mg BID (n = 98) IM 400 or 600 mg QD (n = 96) P Value MR4.5 in pts without MR4.5 at BL (intention to treat analysis) n (%) n (%) By 12 mo 32 (33) 13 (14) 0.0020 By 24 mo 42 (43) 20 (21) 0.0006 By 36 mo 46 (47) 32 (33) 0.0453 By 36 mo, excluding pts who crossed over to NIL 46 (47) 23 (24) 0.0003
