Found in Translation

Under his IDH2: Epigenetic drivers of clonal hematopoiesis


 

The world has surely changed in recent years, leading television and Hollywood to recreate many former works of postapocalyptic fiction. Watching the recent Hulu drama “The Handmaid’s Tale” leads many to make modern-day comparisons, but to this hematologist the connection is bone deep.

Hematopoietic stem cells face a century of carefully regulated symmetric division. They are tasked with the mission to generate the heterogeneous and environmentally responsive progenitor populations that will undergo coordinated differentiation and maturation.1

Dr. Aaron D. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is a clinical instructor, is on the staff of the leukemia service, and is a clinical researcher.

Dr. Aaron D. Viny

Frankly, it is amazing that things only rarely go wrong. Yet, nearly 20,000 people in the United States are diagnosed with acute myelogenous leukemia (AML) annually. As we interrogate the genome and epigenome of AML, we can look back at the key events that led to their coup of a once free and peaceful bone marrow.

Within this epic battle of Gilead, much like hematopoiesis, there is a hierarchy within the Sons of Jacob. At the top there are few who drive leukemogenicity and require no other co-conspirators. MLL fusions and core binding factor are the Commanders that can overthrow the regulated governance of normal marrow homeostasis. Other myeloid disease alleles are soldiers of Gilead (i.e. FLT3-ITD, IDH1, IDH2, NPM1c, Spliceosome/Cohesin). Their individual characteristics can influence the natural history of the disease and define its strengths and weaknesses, particularly as new targeted therapies are developed.

Recently, Jongen-Lavrencic et al. reported that all disease alleles that persist as minimal residual disease after induction have a negative influence on outcome, except for three – DNMT3A, TET2, and ASXL1.2 What do we make of the “DTA” mutations? Are they the “Eye” – spies embedded in the polyclonal background of the marrow – intrinsically wired with malevolent intent? Are they the innocent, abused Handmaids – reprogrammed by inflammatory “Aunts” at the marrow’s Red Center and forced to clonally procreate? Previous works have suggested the latter, that persistence of mutations in genes found in clonal hematopoiesis (CH) do not portend an equivalent risk of relapse.3,4

A more encompassing question remains as to the equivalency of CH in the absence of a hematopoietic tumor versus CH postleukemia therapy. Comparisons to small cell lymphomas after successful treatment of transformed disease are disingenuous; CH is not itself a malignant state.5 Forty months of median follow-up for post-AML CH is simply not enough time. Work presented at the 2017 annual meeting of the American Society of Hematology by Jaiswal et al. showed that the approximately 1% risk of transformation per year was consistent over a 20-year period of follow up in the Swedish Nurse’s Study.

The recent work in the New England Journal of Medicine adds to the growing understanding of CH, but requires the test of time to know if these cells are truly innocent Handmaids or the Eye in a red cloak. I’ll be exploring these issues and taking your questions during a live Twitter Q&A on June 14 at noon ET. Follow me at @TheDoctorIsVin and @HematologyNews1 for more details. Blessed be the fruit.

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