ESH-EHA Scientific Workshop AML "Molecular" 

October 14-16, 2011 - Mandelieu La Napoule, France. Chairs : B. Löwenberg, Hartmut Döhner

Short report by Kimmo Porkka

The meeting was exceptionally good. Central themes were epigenetics (pathogenesis and therapeutics), stem cell niches, FLT3, NPM1. Some brief comments on few of the presentations (the biological part). 

Signaling pathways in leukemic stem cells. S. Armstrong (Boston)

• Examples of a cancer driven by mutations involving an epigenetic regulator are leukemias bearing translocations involving the Mixed Lineage Leukemia (MLL) gene at 11q23. MLL-rearranged leukemias account 10% leukemias (ALL, AML). >70 fusion partners described. Associated with a poor prognosis both in children and in adults
• Speaker studied MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs).
• Loss of Dot1l selectively decreased expression of MLL fusion-driven transcriptional programs. The aberrant H3K79 methylation pattern and the specific requirement of H3K79 methylation for the maintenance of the MLL translocation-associated oncogenic program demonstrated that MLL-rearranged leukemias are driven by an aberrant epigenetic program. This has profound therapeutic implications because Dot1l is one of few enzymes linked to MLL-fusion proteins and, as such, may represent an important therapeutic target.
• Preclinical data on a small molecule Dot1 inhibitor presented, promising
• Related paper: Cancer Cell. 2011 Jul 12;20(1):66-78.
• A nice recent review on MLL: Br J Haematol. 2011 Jan;152(2):141-54

CEBPA mutants, stem cells and leukemogenesis. C. Nerlov (Edinburgh) 

• CEBPA-mutations in 9% de novo AML. A transcription facotor and an epigenetic modulator.
• Combined N- and C-terminal CEBPA-mutations collaborate in leukemogenesis and induce erythroid reprogramming and expansion of pre-leukemic stem cells with sufficient myeloid lineage commitment to generate leukemia initiating cells. In concord, often associated with FLT3-ITD mutations
• Related paper: Cancer Cell. 2009 Nov 6;16(5):390-400.

Molecular basis for APL cure by retinoic acid and arsenic. H. de Thé (Paris)

• Retinoic acid (RA) rapidly induces massive differentiation of blasts into neutrophils in t(15;17) with PML-RARA-fusion in acute promyelocytic leukemia (APL), but rarely if ever cures patients as monotherapy. In combination with an anthracycline/cytarabine cures >80% of APLs.
• Arsenic trioxide had been used in treating malignancies from the 18th to mid-20th century and has been shown to induce complete remissions in APL.
• RA+arsenic curative in mice and in patients: combination synergises for PML-RARA oncogene degradation and rapidly clears leukemia-initiating cells. Oncogene degradation could be a generally applicable strategy to eradicate cancer stem cells in many types of tumors.
• Applicable to other leukemias: addition of RA to chemotherapy improves responses in NPM1-positive AMLs (Haematologica. 2009 Jan;94(1):54-60), combination with arsenic even more effective?
• Related paper: Science. 2010 Apr 9;328(5975):240-3
• Recent reviews from the group: Nat Rev Cancer. 2010 Nov;10(11):775-83, Blood. 2011 Jun 2;117(22):5795-802.

Stress-induced activation of HSC's. A. Trumpp (Heidelberg)

• Virus/tumor-induced IFNa and LPS from gram- bacteria induce cycling of HSC's ina a SCA-1-dependent manner
• Recent paper showing activation of dormant HSC's by IFNa: Nature. 2009 Apr 16;458(7240):904-8.
• Recent review: Nat Rev Immunol. 2010 Mar;10(3):201-9

The vascular niche. D. Sipkins (Chicago)

• A very nice talk on on the BM microenvironment. At least two major HSPC niches exist within the bone marrow — the perivascular niche and the endosteal (or bone) niche.
• In vivo confocal and multiphoton microscopy studies in mice show that leukemic cells hijack the normal HSC niche signalling pathways to enter the BM. Dynamic interplay between leukemia and the BM niche critically regulates leukemic growth and is a therapeutic target.
• Related paper: Science. 2008 Dec 19;322(5909):1861-5
• Related commentary: Cell Stem Cell. 2010 Dec 3;7(6):645-6

Fanconi anemia pathway and AML. K. J. Patel (Cambridge)

• Fanconi anaemia (FA) is a chromosome-breakage disease that causes developmental defects, sterility, bone-marrow failure and a highly elevated risk of cancer, AML in particular. Mutations in 15 genes are known to be associated with this disorder (incl. BRAC2). Cells carrying FA-associated mutations are exceptionally sensitive to the crosslinking agent acetaldehyde, a highly reactive substance and can damage DNA, and can cause crosslinking.
• Patel's work provides strong evidence that metabolically produced acetaldehyde (e.g. from ethanol)  is a potential driver of endogenous DNA damage, which is normally counteracted by acetaldehyde detoxification, in conjunction with DNA repair through the FA pathway.
• Significant implications: ethanol consumption is genotoxic through the accumulation of acetaldehyde, potentially causing fetal damage (for instance, fetal alcohol syndrome), bone-marrow dysfunction and increased prevalence of cancers. Could also be therapeutically utilized in leukemia (preclinical experiments ongoing): ethanol + antabus!
• Related papers from the group: Nature. 2011 Jul 6;475(7354):53-8, Nat Genet. 2011 Feb;43(2):147-5, Science. 2010 Jul 9;329(5988):219-23

Interrogating the architecture of cancer genomes by deep sequencing. P. Campbell (Cambridge)

• Referenced their very nice paper on exome sequencing of 9 MDS RARS patients: N Engl J Med. 2011 Oct 13;365(15):1384-1395

Disease gene identification in preleukemic disorders. O. Bernard (Paris)

• Reviewed his recent paper on TET2-mutations in CMML and lymphomas. Cancer Cell. 2011 Jul 12;20(1):25-38

Small molecule phenotypic screening to identify inducers of megakaryocyte polyploidization as targeted therapy for AML. J.D. Crispino (Chicago)

• Performed a high-throughput screen on >1000 small molecule compounds: AML cells incubated with compunds 72h, fixed, analyzed for moprhology and DNA content (e.g. proliferation, apoptosis) using Cell Profiler software from Broad institute. Identified >200 small molecules, focused on diMF compound, found its target to be ROCK1 kinase. A very promising differentiation therapy for AMKL.

Identification of candidate AML drug targets using. S. Fröhling (Ulm)

• Homeobox gene CDX2 is aberrantly expressed in 90% of acute myeloid leukemia and promotes leukemogenesis
• PPAR gamma agonists (anti-diabetic drugs in development) a novel potential therapeutic agent for CDX2-driven AML 

Methylome mapping of hematopoietic stem cells: epigenetic basis of hematopoietic differentiation and de-differentiation. A. Feinberg (Baltimore)

• A really great and visionary talk, novel concept on the central role of epigenetics in cancer initiation.
• In a comprehensive analysis of common cancer types, a high degree of stochastic variation in methylation within each tumor type, but involving the same loci across tumor types. A hypothesis: stochastic epigenetic variation is a driving force for development, adaptation and disease.     
• For more details, have a look at the related papers: Nat Genet. 2011 Jun 26;43(8):768-75, Nat Struct Mol Biol. 2011 Jul 3;18(8):867-74, Nature. 2010 Sep 16;467(7313):338-42

 

EVI1-positive AML R. Delwel (Rotterdam)

Epigenetic profiling of AML A. Melnick (New York)
MicroRNA profiling G. Marcucci (Columbus)
Identification and characterization of miRNA controlled pathways in AML S. Erkeland (Rotterdam)
Molecular diagnostic stratification C. Bloomfield (Columbus)
CEBPA mutations in AML P. Valk (Rotterdam)
Molecular diagnostic stratification A. Burnett (Cardiff)
NPM1 mutation as a molecular marker to monitor MRD in AML K. Döhner (Ulm)
Flow cytometric MRD assessment : clinical consequences G. Ossenkoppele (Amsterdam)
Combined epigenetic therapy K. Bhalla (Kansas)
Targeting of abnormal repair of double strand breaks F. Rassool (Baltimore)
AML stem cell priming J. Dipersio (Washington)
Identification, characterisation and therapeutic targeting of myelodysplastic syndrome stem cells S. E. W. Jacobsen (Oxford)
Update on FLT3 inhibition T. Fischer (Magdeburg)
Targeting mTOR/protein translation D. Bouscary (Paris)
Pathogenesis and Therapy of IDH‐mutant leukemias R. Levine (New York)
Novel drugs in clinical trial for AML. F. Giles (Galway)