Fig. 2

Inferred phylogenetic tree of mutational process contributing to the sequential appearance of MDS/ET, MS and B-cell ALL. Branch splits are consistent with NGS and FISH data reviewed in Table 1. Notation: Chromosomal aberrations are denoted by a square. Solid squares (filled square) denote presence of chromosome abnormality; open squares (open square) denote their disappearance. X marks denote presence of point mutations, while open circles (circle) denote loss of mutation. The order of mutations between branch splits cannot be inferred from the data and therefore they are listed lexicographically. The founder cell is proposed to be an HSC containing del (5q) as well as somatic driver mutations (ASXL1, JAK2, TET2, TP53, SF3B1). Prior to blast transformation, the pluripotent HSC capable of myeloid and lymphoid differentiation, acquired new KMT2A (MLL) amplification. Absence of MLL amplification in bone marrow suggests this clone seeded into the periphery thereby accounting for its presence in the extramedullary blast transformation but not in the bone marrow. Deletion 17p was present in 2016 accelerated phase ET and appears to have been conserved in the subclone that evolved into myeloid sarcoma. Deletion 20q was first seen in bone marrow after lenalidomide therapy and is present in subclone that evolved into B-cell ALL. Treatment with lenalidomide contributed to the suppression of del(5q) clones in bone marrow but had little effect in extramedullary leukemias