The hematopoietic saga of clonality in sickle cell disease

Abstract

Sickle cell disease (SCD) is associated with an increased risk of vascular-occlusive events and of leukemia. Clonal hematopoiesis (CH) may increase both risks. In turn, physiologic abnormalities in SCD may modify the incidence and/or distribution of genetic alterations in CH. In a recent issue of the JCI , Liggett et al. found no difference in CH rate between individuals with versus without SCD. Here we contextualize this report and discuss the complex interplay between CH and SCD with particular attention to consequences for emerging gene therapies. We further consider the limitations in our current understanding of these topics that must be addressed in order to optimize therapeutic strategies for SCD.

Is There any Relationship Between the Repeated Complications of Sickle Cell Disease and the Potential Development of Acute Leukemia?

“…Although the leukemic risk of hydroxyurea (HU), which remains a therapeutic mainstay in the treatment of SCD, has never been confirmed in large series of patients [ 11 – 13 ] and has not been associated with an increased risk of clonal hematopoiesis [ 14 ], the potential risk following a conditioning regimen for HSC transplantation remains more questionable. There is a real possibility that the medley of high-risk clonal hematopoiesis and HSC transplantation incites mutant clones to expand and subsequently transform [ 15 ].…”

“…Many questions remain open about cancer risk in patients with SCD, especially those living well into adulthood. Although several mechanisms potentially involved in the leukemic transformation have been discussed [ 15 , 22 , 26 ], somatic mutations identified at the time of leukemia diagnosis appear likely to be related to a lifetime of erythropoietic stress and inflammation. New large studies involving SCD patients tested with a large panel of mutations frequently involved in clonal hematopoiesis and using highly sensitive assays are still required.…”

Sickle Cell Disease, a Review

“…Signaling pathways in the erythrocytes can be modulated by hypoxia, stress, and inflammatory response which can influence activation of the adhesion receptors [6,[19][20][21][22][23][24]. Clonal hematopoiesis (CH) can potentially increase risk of vascular occlusive events and development of leukemia [25]. Physiologic abnormalities in this disease can modify the incidence and distribution of genetic alterations in CH [25].…”

“…Clonal hematopoiesis (CH) can potentially increase risk of vascular occlusive events and development of leukemia [25]. Physiologic abnormalities in this disease can modify the incidence and distribution of genetic alterations in CH [25].…”

Reply to R. Meisel

“…2 In addition, we propose approaches for consideration in the context of hematopoietic cell transplantation and other curative treatments for sickle cell disease: (1) systematic examination of pretransplant biospecimens for myeloid mutations, mutations in DNA damage response genes (TP53, PPM1D, and CHEK2); (2) sequential sampling to study DNA damage response clones after allogeneic hematopoietic cell transplantation or gene therapy/gene editing; and (3) sequential examinations for proinflammatory markers and markers for hemolysis. [5][6][7] We acknowledge that these approaches require substantial investment from governmental agencies and/or industry partners. One such example is the Cure Sickle Cell Initiative by the National Heart Lung and Blood Institute in the United States.…”