11q deletion in hematological malignancies


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Written 2022-02-13 Miguel Quijada Álamo
Universidad de Salamanca


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Deletions of the long arm of chromosome 11 (del(11q)) have been detected in a number of patients suffering from different types of hematological malignancies. The vast majority of these abnormalities encompass the chromosomal bands 11q22 and 11q23, suggesting that these particular regions contain a tumor suppressor(s) gene(s) that can be involved in the pathogenesis of such disorders1. Interestingly, the presence of del(11q) is only concentrated in some subtypes of hematological cancers, where it is detected at a relatively high frequency. For instance, del(11q) is highly prevalent in two specific B-cell lymphoproliferative disorders: chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Indeed, this chromosomal abnormality can be detected in approximately 20% and 50% CLL and MCL cases at diagnosis, respectively1-4. Although far less frequent, del(11q) can also be detected in other B-cell neoplasms such as Waldenström?s macroglobulinemia (WM) (7%) and follicular lymphoma (FL) (5%), whereas telomeric 11q losses in addition to other 11q abnormalities have been reported in Burkitt lymphoma (BL)5-7. Moreover, deletions of the long arm of chromosome 11 are frequent in T-cell prolymphocytic leukemia (T-PLL), where it accounts for more than 50% of cases 8,9. In myeloid malignancies, the presence of del(11q) is rare, although it has been reported to be a clonal abnormality in 1-3% of patients with a myelodysplastic syndrome (MDS)10.

In CLL, patients harboring a del(11q) are usually young and often present a disease characterized by a bulky lymphadenopathy, rapid disease progression and reduced overall survival under chemotherapy-based regimes2,3,11. The presence of del(11q) is exclusively monoallelic, and the size of this deletion is highly variable, usually spanning more than 20 megabases (Mb) in size. The implementation of high-resolution SNP arrays has revealed that the vast majority of del(11q) CLL cases have a common minimally deleted region (MDR) of 2-3 Mb, encompassing the tumor suppressor gene ATM, a central regulator of the DNA damage response signaling, located at 11q22.312. Traditionally, it has been considered that ATM deletion is one of the main responsible events for the pathobiology of del(11q) in CLL, and this is supported by the fact that one third of del(11q) patients harbor deleterious ATM mutations in the remaining allele, having as a consequence a biallelic ATM loss and a complete ATM dysfunction12,13. In addition, BIRC3, a negative regulator of the NF-?B signaling located at 11q22.2, has also a role in the pathobiology of this cytogenetic abnormality in CLL. This gene is deleted in 80% of del(11q) cases and can also be biallelically affected through truncating mutations in the remaining allele12,14. Moreover, it has been suggested that the haploinsufficiency of other genes located in 11q22.3 (i.e. RDX, FDX1, RAB39, CUL5, ACAT1, NPAT, KDELC2, EXPH5, MRE11, HA2XF and PPP2R1B) might play a role in del(11q) pathogenesis, although further studies are required to fully validate the biological impact of these candidates15.

As opposed to CLL, del(11q) does not account for a reduced survival of MCL cases. In this disease, two different MDRs affecting 11q22.2 and 11q23.3 have been reported, respectively, also affecting ATM among other genes16. In addition, ATM and BIRC3 mutations have also been detected in del(11q) MCL cases, indicating a possible role of both this genes in the pathobiology of this type of lymphoma17. In the case of WM, the MDR of del(11q) also encompasses the tumor suppressor ATM, and the presence of this deletion is associated with adverse clinical and biological parameters, although it does not show an impact in progression-free or overall survival18]. In FL, the pattern of deletions of the long arm in chromosome 11 is more complex, involving chromosomal bands 11q13.3, 11q23.1 or 11q23.3. The MDR region for FL cases harboring 11q13.3 losses includes FADD, a gene involved in the apoptotic pathway. On the other hand, the MDR of losses affecting 11q23.1 includes ATM in most cases, as well as downstream genes such as ARHGAP20. In addition, FL cases harboring 11q23.3 deletion encompass TAGLN and PCSK7 genes within their MDR6. Furthermore, telomeric losses of 11q24 in combination with 11q23 amplifications have been found in a particular subset of BL patients, characterized by the absence of MYC abnormalities7.

In the case of T-PLL, 11q deletions include chromosomal bands 11q22.3-23.1, and the MDR always encompasses the ATM gene. In a similar way to CLL, ATM mutations are also common in T-PLL, resulting in a complete biallelic inactivation of ATM in del(11q) T-PLL cases8,9. Nevertheless, the presence of this cytogenetic abnormality does not have a prognostic significance in patients suffering from this type of T-cell disorder19. Finally, in myeloid malignancies, del(11q) MDS patients share a common MDR affecting chromosomal band 11q23 and including ATM, CADM1, CBL and KMT2A as possible candidate driver genes within this abnormality10.

Citation

Miguel Quijada Álamo

Atlas of Genetics and Cytogenetics in Oncology and Haematology 2022-02-13

11q deletion in hematological malignancies

Online version: http://atlasgeneticsoncology.org/teaching/208957/11q-deletion-in-hematological-malignancies