Del(5q): gene dosage matters

In this issue of Blood, Joslin and colleagues provide new evidence that EGR1 haploinsufficiency may contribute to myeloid diseases associated with loss of a whole chromosome 5 or a deletion of the long arm, del(5q).

Del(5q) is one of the most common cytogenetic abnormalities found in de novo and therapy-related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The potential importance of del(5q) as an early or initiating genetic event in MDS is highlighted by the sensitivity of del(5q) clones (occurring either alone or with complex karyotypes) to treatment with lenalidomide.¹  Over the past decade, work by Le Beau²  and others has implicated haploinsufficiency of a gene or genes on chromosome 5q31, rather than homozygous deficiency for a gene, as a mechanism for pathogenesis. Recent evidencesupporting this hypothesis suggests that reduced expression of CTNNA1, a gene on the del(5q) interval, is important in del(5q)-associated MDS and AML.³  Now, Joslin and colleagues demonstrate that haploinsufficiency of Egr1, another gene on the human del(5q) interval, plays a role in the development of myeloid disease in mice.

Joslin and colleagues thoroughly characterized the hematopoiesis of Egr1 heterozygous and homozygous knock-out mice under normal physiologic conditions, which showed no differences compared with wild-type mice. The authors went on to treat Egr1 mutant mice with a single dose of N-ethyl-nitrosourea (ENU), a prototypical alkylating agent, in order to induce secondary cooperating mutations. ENU-treated Egr1^+/– and Egr1^–/– mice both developed T-cell lymphomas and a myeloproliferative disease (MPD) at higher frequencies than ENU-treated wild-type mice (see figure). The MPD phenotype resembles the MDS/MPD overlap disease of humans. Thus, the data suggest that loss of 1 copy of Egr1 contributes to myeloid disease in mice by cooperating with unidentified, ENU-induced mutations.

The identification of critical genes in the 5q31 region that contribute to MDS or AML has been hampered by the difficulty of studying haploinsufficiency as a mechanism of disease pathogenesis. This study elegantly explores the effect of gene haploinsufficiency, but also highlights the difficulty of modeling myeloid diseases in mice. Although myeloid disease was only minimally increased in Egr1^+/– mice treated with ENU, it is possible that the contribution of Egr1 haploinsufficiency to myeloid disorders is underestimated due to the propensity of this mouse strain (C57BL/6) to develop lymphomas when treated systemically with ENU.⁴  In addition, ENU treatment predominantly induced an MPD phenotype in these mice rather than MDS or AML, which may also be modified by studying Egr1 haploinsufficiency in a mouse strain susceptible to ENU-induced AML and MDS.³  Although the mechanism of disease initiation in Egr1-haploinsufficient hematopoietic cells is unknown, there is precedent for Egr1 behaving as a tumor suppressor in other cancer models. This study adds to the growing list of genes implicated in hematologic malignancies that act as tumor suppressors in the haploinsufficient state. Importantly, the findings also raise the possibility that decreased expression of multiple del(5q) genes may be necessary for disease initiation, and highlight the need to develop whole-genome approaches to identify additional cooperating mutations in MDS and AML in mice and humans.