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INGRAIN-MF
Incorporating genetics, risk and associated burden into MF management

MODULE 2: The influence of genetic factors in myelofibrosis

Non-driver mutations in myelofibrosis

The three driver mutations are not sufficient to describe the full molecular and phenotypic heterogeneity of myelofibrosis (MF) - typically, three or more somatic mutations are also found.1,2 These acquired mutations have been identified using next-generation sequencing (NGS) and other whole-genome analysis techniques. However, unlike the driver mutations, they are not restricted to MPNs, and in fact are more frequently found in myelodysplastic syndromes (MDSs) and acute myeloid leukaemia (AML).2

Most of the non-driver MF mutations are involved in phenotypic changes and disease progression.2

Non-driver somatic mutations in MF2,3

  Mutated gene Function Incidence in primary MF Incidence in MPN: ET+PV+MF
Signalling LNK Negative regulator of JAK2 2%  
CBL Cytokine receptor internalisation 4%  
Histone modifications EZH2 H3K27 methyltransferase 5%-10%  
ASXL1 Chromatin binding protein associated with PRC1 and 2 25%-36%  
RNA splicing U2AF1 U2 small nuclear RNA-slicing factor 10%-16%  
SRSF2 Serine/ arginine-rich pre-RNA splicing factor 10%-18%  
DNA methylation TET2 Alpha-ketoglutarate-dependent dioxygenase 18% 10%-20%
DNMT3A DNA methylase 9% 5%-10%
IDH1 Neomorphic enzyme 1%-3%  
IDH2 Neomorphic enzyme 1%-3%  

Adapted from Vainchenker W and Kralovics R, 20172 and Tefferi A et al, 20163

ET: essential thrombocythaemia; MPN: myeloproliferative neoplasm; PV: polycythaemia vera

Occurrence of non-driver mutations in 182 patients with primary MF3

NGS with a myeloid neoplasm-relevant 27-gene panel was performed on bone marrow or whole blood DNA from 182 patients diagnosed with primary MF. 81% of patients were found to have mutations in genes other than JAK2, MPL and CALR.

Driver mutation distribution

Number of non-driver mutations

The most frequent non-driver mutation was ASXL1 (36%), followed by TET2 (18%), SRSF2 (18%) and U2AF1 (16%).

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References
  1. Rumi E, Pietra D et al. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood 2014;124(7):1062-1069
  2. Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood 2017;129(6):667-679
  3. Tefferi A, Lasho T L et al. Targeted deep sequencing in primary myelofibrosis. Blood Adv 2016;1(2):105-111