The myelodysplastic syndromes (MDS) are a hetero- generous group of clonal stem-cell disorders

characterized by ineffective hematopoiesis, abnormal cellular morphology, and a propensity for progression
to acute leukemia.

MPNs are rare hematological conditions (pre-leukemic states/disorders). Arose/occurred due to the defects
in clonal HSCs (carrying somatic mutations in leukemia prone genes) which is characterized by aberrant
proliferation/expansion of mature blood components generated from myeloid lineages ().

The MPNs categorized into two major subgroups based on the presence or absence of BCR-ABL fusion
oncogene (Ph+/-) such as Chronic myeloid leukemia (CML) (BCR-ABL+) while absence of this gene in
polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) (). The latter
subtypes are well characterized by the presence of a JAK2 somatic mutation (G to T) at nucleotide 1849/exon
14 leading to the replacement of valine to phenylalanine at codon 617 (JAK2V617F) which comprises more
than 90% parts of PV and about 25-30% of ET and PMF ().

PKM is a rate-limiting glycolytic enzyme, and previous studies have shown that PKM1 is found mainly in
normal cells, whereas PKM2 is an embryonic-isoform expressed in cancer cells.

Pyruvate kinase M2 is a critical enzyme that regulates cell metabolism and growth under different
physiological conditions. In its metabolic role, pyruvate kinase M2 catalyzes the last glycolytic step which
converts phosphoenolpyruvate to pyruvate with the generation of ATP.

The binding leads to nuclear translocation of PKM2, where it acts as protein kinase and interacts with other
molecules to control the expression of vascular endothelial growth factor (VEGF), thereby promoting tumor
angiogenesis (61). Under the hypoxic condition, translocation of PKM2 and p65 to the nucleus takes place.

PKM2 expression is associated with increased glucose uptake, increased lactate production, and decreased
O2 consumption, which can be reversed by genetic manipulations that replace PKM2 expression with PKM1.
Therefore, PKM2, but not PKM1, promotes the Warburg effect.

Lactate dehydrogenase (LDH), which catalyzes conversion of pyruvate into lactate, serves a critical role during
Warburg effect. LDH A chain (LDHA), a member of the LDH family, is upregulated in multiple types of cancer
and serves a vital role in tumor growth and progression

Myc expression was positively related to LDHA, and knock- down of c‐Myc could inhibit LDHA expression,
15 16
impairing lactate production and glucose consumption. Intriguingly, Zhang et al found that inhibition of
LDHA increased c‐Myc expression, suggesting that LDHA had a negative feedback on c‐Myc expression.